Glioblastoma, Glioblastoma Multiforme, Gliosarcoma
Conditions
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.
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
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
Sponsors
University of California, San Francisco
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1- Determination of the Maximum Tolerated Dose (MTD) of Enzastaurin | Until MTD can be determined (up to 12 cycles, 28 days per cycle) | 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) | Baseline to death from any cause (Up to 48 weeks) | 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
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 - Response Rate With Macdonald Criteria | Baseline, following radiation, every other cycle (up to 12 cycles, 28 days per cycle) | 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) | Every cycle (28 days per cycle) | 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 | Each radiologic assessment (up to 12 cycles, 28 days per cycle) | Number of patients having MRI/MRS for clinical evaluation with baseline assessment. |
| Phase 1 and 2 - Progression-Free Survival (PFS) | Baseline to measured progressive disease (up to 12 cycles, 28 days per cycle) | PFS was defined as the time from date of first dose to the first observation of disease progression, or death due to any cause. |
| Phase 1 - Number of Participants With Adverse Events (AEs) | Every cycle (up to 12 cycles, 28 days per cycle) | Summaries of serious AEs (SAEs) and all other non-serious AEs are located in the Reported Adverse Event Module. |
| M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Every cycle (up to 12 cycles, 28 days per cycle) | 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 | Cycle 1 Day 22, Cycle 2 Day 5, 28 days per Cycle | 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 | 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 | 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 (%). |
| Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Every cycle (up to 12 cycles, 28 days per cycle) | 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. |
| Phase 1 and 2: Association Between Biomarkers and Clinical Outcome | Baseline, Cycle 2, end of study (up to 12 cycles, 28 days per cycle) | 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. |
Countries
United States
Participant flow
Pre-assignment details
A total of 12 participants entered Phase 1 of the study. A total of 60 participants were analyzed in Phase 2 for a total of 72 participants for both phases.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1- Cohort 1 (250 mg Enzastaurin) Participants who received 250 mg enzastaurin in Phase I with 75 mg/m\^2 temozolomide and radiotherapy. | 6 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) Participants who received 500 mg enzastaurin in Phase I with 75 mg/m\^2 temozolomide and radiotherapy. | 6 |
| Phase 2 Participants who received 250 mg enzastaurin in Phase II with 75 mg/m\^2 temozolomide and radiotherapy. | 60 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 6 |
| Overall Study | decline related hyponatremia/tumor | 0 | 0 | 1 |
| Overall Study | Disease Progression | 0 | 4 | 38 |
| Overall Study | Jaw infection after surgery-other | 1 | 0 | 0 |
| Overall Study | mistaken thrombocytopenia | 0 | 0 | 1 |
| Overall Study | other complicating disease | 0 | 0 | 2 |
| Overall Study | Treatment completed per protocol | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 5 |
Baseline characteristics
| Characteristic | Phase 1- Cohort 1 (250 mg Enzastaurin) | Phase 1 Cohort 2 (500 mg Enzastaurin ) | Phase 2 | Total |
|---|---|---|---|---|
| Age, Continuous | 48.0 years STANDARD_DEVIATION 7.54 | 52.5 years STANDARD_DEVIATION 13.84 | 55.3 years STANDARD_DEVIATION 10.95 | 54.7 years STANDARD_DEVIATION 10.85 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 3 Participants | 52 Participants | 61 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 60 Participants | 72 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 17 Participants | 21 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 43 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 60 / 60 |
| serious Total, serious adverse events | 0 / 6 | 1 / 6 | 22 / 60 |
Outcome results
Primary
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)
Population: Phase 2 participants combined with Phase 1 cohort 1 participants who also received 250 mg enzastaurin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Participants | Phase 1 and Phase 2 - Overall Survival (OS) | 18.3 months |
Primary
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)
Population: All Phase I participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Participants | Phase 1- Determination of the Maximum Tolerated Dose (MTD) of Enzastaurin | 250 milligrams (mg) |
Secondary
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)
Population: All treated participants who received at least one dose of study drug in the 250 mg enzastaurin cohort from Phases 1 and 2 combined and who also provided FACT-Br data from at least 1 visit (N = 65). One participant lacked these data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Baseline visit | 153.5 units on a scale | Standard Deviation 24.08 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Radiation therapy visit | 156.1 units on a scale | Standard Deviation 23.3 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 1 | 151.9 units on a scale | Standard Deviation 26.87 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 2 | 152.0 units on a scale | Standard Deviation 30.67 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 3 | 158.9 units on a scale | Standard Deviation 22.1 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 12 | 163.5 units on a scale | Standard Deviation 26.67 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 4 | 158.8 units on a scale | Standard Deviation 24.48 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 5 | 158.3 units on a scale | Standard Deviation 26.3 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 6 | 159.0 units on a scale | Standard Deviation 26.46 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 7 | 164.1 units on a scale | Standard Deviation 19.45 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 8 | 163.6 units on a scale | Standard Deviation 23.19 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 9 | 162.0 units on a scale | Standard Deviation 21.89 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 10 | 159.3 units on a scale | Standard Deviation 27.02 |
| Phase 1 Participants | Functional Assessment of Cancer Therapy - Brain (FACT-Br) | Cycle 11 | 158.2 units on a scale | Standard Deviation 24.98 |
Secondary
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 8 | 2.6 units on a scale | Standard Deviation 2.4 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Radiation therapy visit | 3.3 units on a scale | Standard Deviation 2.1 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Baseline | 2.4 units on a scale | Standard Deviation 2.1 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 5 | 3.3 units on a scale | Standard Deviation 2.5 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 10 | 1.9 units on a scale | Standard Deviation 1.9 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 2 | 3.7 units on a scale | Standard Deviation 2.7 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 3 | 3.2 units on a scale | Standard Deviation 2.5 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 6 | 2.9 units on a scale | Standard Deviation 2.4 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 11 | 3.0 units on a scale | Standard Deviation 2.8 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 1 | 3.6 units on a scale | Standard Deviation 2.5 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 12 | 1.7 units on a scale | Standard Deviation 1.8 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 7 | 2.8 units on a scale | Standard Deviation 2.4 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 9 | 2.8 units on a scale | Standard Deviation 2.5 |
| Phase 1 Participants | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 4 | 2.6 units on a scale | Standard Deviation 2.1 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 1 | 2.4 units on a scale | Standard Deviation 2.6 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 8 | 1.4 units on a scale | Standard Deviation 1.5 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 9 | 1.8 units on a scale | Standard Deviation 1.6 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 10 | 1.5 units on a scale | Standard Deviation 1.9 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 3 | 2.0 units on a scale | Standard Deviation 1.9 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Baseline | 1.8 units on a scale | Standard Deviation 2.6 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 4 | 1.9 units on a scale | Standard Deviation 1.6 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Radiation therapy visit | 2.2 units on a scale | Standard Deviation 2.3 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 5 | 2.1 units on a scale | Standard Deviation 2.4 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 12 | 1.2 units on a scale | Standard Deviation 0.9 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 6 | 1.6 units on a scale | Standard Deviation 1.3 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 2 | 2.5 units on a scale | Standard Deviation 3 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 7 | 1.4 units on a scale | Standard Deviation 1.3 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 11 | 1.6 units on a scale | Standard Deviation 2.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 9 | 1.0 units on a scale | Standard Deviation 1.9 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 1 | 1.6 units on a scale | Standard Deviation 2.4 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 2 | 1.8 units on a scale | Standard Deviation 2.5 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 3 | 1.4 units on a scale | Standard Deviation 2.3 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 4 | 1.0 units on a scale | Standard Deviation 1.8 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 5 | 0.6 units on a scale | Standard Deviation 1.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 6 | 0.7 units on a scale | Standard Deviation 1.2 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 7 | 0.7 units on a scale | Standard Deviation 1.4 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 8 | 0.5 units on a scale | Standard Deviation 0.9 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 10 | 0.4 units on a scale | Standard Deviation 1.2 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 11 | 0.2 units on a scale | Standard Deviation 0.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 12 | 0.4 units on a scale | Standard Deviation 0.7 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Baseline | 0.3 units on a scale | Standard Deviation 1.1 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Radiation therapy visit | 1.0 units on a scale | Standard Deviation 1.9 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 2 | 1.9 units on a scale | Standard Deviation 2.2 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 11 | 0.9 units on a scale | Standard Deviation 1.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 6 | 1.2 units on a scale | Standard Deviation 1.7 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 5 | 1.6 units on a scale | Standard Deviation 2.1 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 1 | 1.8 units on a scale | Standard Deviation 2.2 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 12 | 1.2 units on a scale | Standard Deviation 1.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 4 | 1.5 units on a scale | Standard Deviation 1.6 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 3 | 1.5 units on a scale | Standard Deviation 1.8 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Radiation therapy visit | 1.4 units on a scale | Standard Deviation 1.7 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 9 | 1.1 units on a scale | Standard Deviation 1.5 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 10 | 1.2 units on a scale | Standard Deviation 1.3 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Baseline | 1.2 units on a scale | Standard Deviation 1.9 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 8 | 1.1 units on a scale | Standard Deviation 1.3 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | M.D. Anderson Symptom Inventory - Brain Tumor (MDASI-BT) | Cycle 7 | 1.3 units on a scale | Standard Deviation 1.6 |
Secondary
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)
Population: 35 patients underwent MRI and had baseline measurement.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Participants | Number of Participants Undergoing Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS) for Clinical Evaluation at Baseline | 35 Participants |
Secondary
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)
Population: Combined Phases 1 and 2 populations for whom IHC scores were obtained. HR \> 1 indicates poorer overall survival for that IHC score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Participants | Phase 1 and 2: Association Between Biomarkers and Clinical Outcome | S6 2211 score | 1.70 Hazard ratio |
| Phase 1 Participants | Phase 1 and 2: Association Between Biomarkers and Clinical Outcome | S6 2215 score | 1.69 Hazard ratio |
Secondary
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
Population: Pharmacokinetic analyses were conducted for individual participants who received at least one dose of study drug and had pharmacokinetic samples collected. In Phase I, one participant dose was reduced from 500 mg to 250 mg after Cycle 1 Day 1 so was included in 250 mg dose group (N=7).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Participants | 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 | Enzastaurin | 5390 nmol•h/L | Geometric Coefficient of Variation 57 |
| Phase 1 Participants | 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 | Total Analyte | 12800 nmol•h/L | Geometric Coefficient of Variation 41 |
| Phase 1 Participants | 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 | LY326020 | 7260 nmol•h/L | Geometric Coefficient of Variation 35 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | LY326020 | 7380 nmol•h/L | Geometric Coefficient of Variation 22 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | Enzastaurin | 5270 nmol•h/L | Geometric Coefficient of Variation 36 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | Total Analyte | 12800 nmol•h/L | Geometric Coefficient of Variation 19 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | LY326020 | 12800 nmol•h/L | Geometric Coefficient of Variation 38 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | Enzastaurin | 7720 nmol•h/L | Geometric Coefficient of Variation 91 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | Total Analyte | 21400 nmol•h/L | Geometric Coefficient of Variation 53 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | Enzastaurin | 16600 nmol•h/L | Geometric Coefficient of Variation 274 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | Total Analyte | 21300 nmol•h/L | Geometric Coefficient of Variation 256 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | LY326020 | 4240 nmol•h/L | Geometric Coefficient of Variation 283 |
| Enzastaurin 500 mg + Temozolomide | 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 | LY326020 | 8650 nmol•h/L | Geometric Coefficient of Variation 95 |
| Enzastaurin 500 mg + Temozolomide | 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 | Enzastaurin | 10100 nmol•h/L | Geometric Coefficient of Variation 133 |
| Enzastaurin 500 mg + Temozolomide | 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 | Total Analyte | 18900 nmol•h/L | Geometric Coefficient of Variation 114 |
Secondary
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)
Population: Phase 2 participants combined with Phase 1 cohort 1 participants who also received 250 mg enzastaurin.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Participants | Phase 1 and 2 - Progression-Free Survival (PFS) | 10.6 months |
Secondary
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)
Population: All Phase I participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Participants | Phase 1 - Number of Participants With Adverse Events (AEs) | 0 Participants |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | Phase 1 - Number of Participants With Adverse Events (AEs) | 1 Participants |
Secondary
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
Population: Pharmacokinetic analyses were conducted for individual participants who received at least one dose of study drug and had pharmacokinetic samples collected. One participant dose was reduced from 500 mg to 250 mg after Cycle 1 Day 1 so is included in the 250 mg dose group (N=7).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Participants | 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 | Enzastaurin | 504 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 52 |
| Phase 1 Participants | 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 | Total Analyte | 853 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 44 |
| Phase 1 Participants | 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 | LY326020 | 370 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 38 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | Enzastaurin | 458 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 41 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | Total Analyte | 821 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 28 |
| Phase 1 Cohort 2 (500 mg Enzastaurin ) | 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 | LY326020 | 392 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 27 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | LY326020 | 198 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 274 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | Enzastaurin | 1350 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 149 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Appetite | 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 | Total Analyte | 1570 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 159 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | Enzastaurin | 719 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 114 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | Total Analyte | 1010 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 114 |
| Enzastaurin 250 mg Phase 1 and 2 Combined-Concentration | 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 | LY326020 | 465 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 87 |
Secondary
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)
Population: Efficacy analysis in phase I was not conducted. Instead, participants who took 250mg in phase I were pooled with phase II participants and are presented in other outcome measures (2 and 8, respectively) in this record. Thus there were 0 participants for this measure.
Secondary
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)
Population: All Phase 2 participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Participants | Phase 2 - Number of Participants With Adverse Events (AEs) | 22 Participants |