| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glioblastoma Multiforme (GBM) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b: To determine the safe and tolerable Phase 2 dose of LY2157299 in combination with radiochemotherapy with temozolomide (TMZ) in patients with glioma.
Phase 2a: To confirm the tolerability and evaluate the pharmacodynamic effect of LY2157299 in combination with standard radiochemotherapy treatment in patients with newly diagnosed GBM (as measured by changes in response biomarkers and their relationship to clinical benefit [for example, 12-month overall survival rate]).
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| E.2.2 | Secondary objectives of the trial |
• Determine clinical benefit (for example, overall survival rate at 12 months, median OS, response rate, median PFS) of the radiochemotherapy treatment when combined with LY2157299
• Population pharmacokinetics of LY2157299
• Determine pharmacodynamic markers in tumor tissue (pSMAD and other TGF-β-related biomarkers, O6-methylguanine-DNA methyltransferase (MGMT) promoter status, and other relevant tumor genetic information)
• Determine serum/plasma and T cell biomarker responses, such as S100β, LDH, TGF-beta, PF4 and T regulatory cell counts.
• Health Outcome Measures, such as the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) and assessment of neurocognitive function. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible only if they meet all of the following criteria:
[1] Patients with histologically proven, newly diagnosed and untreated intracranial GBM including lower grade glioma which evolved into GBM and who have not received any radiochemotherapy (Phase 1b and 2a) or who have WHO Grade III and IV malignant glioma (e.g., AA, AO, AOA) (Phase 1b only) and for Phase 2a, only WHO Grade IV will be eligible for this protocol (Louis et al. 2007).
[2] A biopsy or resection must have been performed no more than 6 weeks prior to treatment. During Phase 1b, the interval may be greater than 6 weeks.
• One or two stained slides from the stereotactic biopsy or open surgery must be available for central pathology review to confirm the original diagnosis.
• If available an FFPE tissue block or unstained slides are to be submitted for pharmacodynamic assessment. If a sample is not available, such a patient will be kept in study and this will not constitute a protocol violation. Additional patients may be enrolled to the trial to ensure an appropriate number of samples are available for the evaluation of the pharmacodynamic markers.
[3] An MRI must be obtained within 72 hours after surgery, preferably within 48 hours. In exceptional situations, the MRI can also be performed up to 96 hours after surgery. In such cases the investigators must deem the MRI image acceptable for subsequent assessments. Patients without measurable or assessable disease are eligible.
For Part 1b, failure of taking the MRI image in the prescribed interval will not constitute a protocol violation, because the objective is on safety.
For Part 2a, failure of taking the MRI image in the prescribed interval will require the addition of a patient to this study to ensure sufficient numbers to assess responses.
[4] Patient must not have had prior cranial RTX.
[5] Patients must not have received prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors. Patients who received Gliadel® wafers at the time of original resection will be excluded.
[6] Patients must plan to begin partial brain radiotherapy within 2-6 weeks after surgery. Regular fractionated radiotherapy with photons (in any planning mode and possibly image-guided or stereotactic if deemed necessary) is performed according to the discretion of the investigator. During Phase 1b, the interval may be greater than 6 weeks.
[7] Patients must be willing to forego other cytotoxic and noncytotoxic drug therapy against the tumor while being treated with LY2157299 and TMZ.
[8] All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.
[9] Patients must be >18 years old
[10] Patients must have performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale (see Protocol Attachment JBAI.5.)
[11] Patients must have adequate organ function, demonstrated by the following tests, which must be performed within 14 days prior to treatment:
• Adequate bone marrow reserve: white blood cell (WBC) count 3.0 109/L, absolute neutrophil count (ANC) 1.5 109/L, platelet count 100.0 109/L, and hemoglobin 10.0 g/dL (6.2 mmol/L). Eligibility level for hemoglobin may be reached by transfusion, if the hemoglobin is 9.0 g/dL.
• Hepatic: bilirubin 2.0 times the upper limit of normal (ULN); alkaline phosphatase (ALP), aspartate transaminase (AST/SGOT), and alanine transaminase (ALT/SGPT) 2.5 times ULN. Should only one of the two transaminases elevated and the other normal, the investigator must rule out a unexpected liver disease prior to enrolling patients on the study.
• Renal: serum creatinine 1.5 times ULN (or calculated creatinine clearance >60 cc/min) before starting therapy.
[12] Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device) during and for up to 6 months after discontinuation of study treatment. Women of childbearing potential must have a negative -HCG pregnancy test documented within 14 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately |
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| E.4 | Principal exclusion criteria |
Patients will be excluded if they meet any of the following criteria:
[13] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or not approved use of a drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[14] Have moderate or severe cardiac disease as defined by any of the following:
• Have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension.
• Have documented major electrocardiogram (ECG) abnormalities that are symptomatic and are not medically controlled (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle branch blocks, ventricular hypertrophy, or recent myocardial infarction).
• Have major abnormalities documented by echocardiography with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction (LVEF) <50%, evaluation based on the institutional lower limit of normal). For additional details, refer to echocardiography protocol (Protocol Attachment JBAI.7).
• Have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by CT scan with contrast).
[15] Are unable to swallow tablets or capsules.
[16] Are pregnant or breastfeeding.
[17] Have any significant medical illnesses that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy.
[18] Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and stopped all therapy for that disease for a minimum of 3 years are ineligible.
[19] Have active infection that would interfere with the study objectives or influence the study compliance.
[20] Stereotactic radiosurgery, such as Gamma-Knife treatment, and brachytherapy are not allowed in this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: Safe and tolerable Phase 2 dose of LY2157299.
Phase 2a: To confirm the tolerability and evaluate the pharmacodynamic effect of LY2157299 in combination with standard radiochemotherapy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1: Baseline to phase 1 completion
Phase 2: Baseline through discontinuation from any cause |
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| E.5.2 | Secondary end point(s) |
Phase 1:
- Pharmacokinetics
Phase 2:
- Overall Survival at 12 Months |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
- Baseline, prior to first dose of cycle 1 and 2 and on days 1,3,8, 14, 15
and 16
Phase 2:
- Randomization to date of death from any
cause at 12 months |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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