| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glioblastoma - a primary brain tumour |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to determine the relative efficacy of cediranib (either in monotherapy or in combination with oral lomustine ) compared to oral lomustine alone by assessment of progression free survival (PFS) as assessed by independent radiographic radiological review. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine the relative efficacy of cediranib (either in monotherapy or in combination with oral lomustine) compared to oral lomustine alone by assessment of Overall Survival (OS)
2. To determine the relative efficacy of cediranib (either in monotherapy or in combination with oral lomustine) compared to oral lomustine alone by assessment of radiographic Response Rate (RR).
3. To determine the relative efficacy of cediranib (either in monotherapy or in combination with oral lomustine ) compared to oral lomustine alone by assessment of alive and progression free rate at 6 months defined as 24 weeks (APF6), after randomisation
4. To determine the steroid sparing effects of cediranib (either in monotherapy or in combination with oral lomustine) compared to oral lomustine alone by assessment of average daily steroid dosage change from baseline until progression and average number of progression/steroid free days.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent
2. Age ≥18 years
3. Life expectancy ≥ 12 weeks
4. Histological/cytological confirmation of glioblastoma
5. Patients with measurable disease (contrast-enhancing tumour ≥10 mm by shortest diameter on 2 axial slices) by MRI imaging within 4 weeks prior to enrolment (Visit 1). Or patients who have undergone a resection without measurable disease prior to enrolment.
6. Patients must have been on no steroids or a stable dose of steroids for at least 5 days before the baseline MRI (Visit 2)
7. Patients must have received only one prior systemic chemotherapy regimen and this regimen must contain temozolomide. In addition, Gliadel® wafers are permitted, as it is part of local treatment.
8. Patients must have a Karnofsky Performance Score of 70 or above
9. Patients must have a mini-mental status examination score of 15 or greater
10. Patients who require either oral anticoagulants (coumadin, warfarin) or low molecular weight heparin are eligible provided there is increased vigilance with respect to monitoring INR.
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|
| E.4 | Principal exclusion criteria |
1. Patients on enzyme-inducing anti-epileptic drugs within 2 weeks prior to randomisation.
- Note: Patients are eligible if they switched to non-enzyme inducing agents and discontinued enzyme-inducing agents for more than or equal to 2 weeks prior to randomisation.
2. Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count ≤1.5 x 109 /L or platelet count ≤100 x 109 /L or requiring regular blood transfusions to maintain haemoglobin >9g/dL
3. Serum bilirubin ≥ 1.5 x ULRR (except for patients with known documented cases of Gilbert’s Syndrome)
4. ALT or AST ≥ 2.5 x ULRR.
5. Serum creatinine > 1.5 x ULRR or a creatinine clearance of ≤ 50mL/min calculated by Cockcroft-Gault
6. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein < 1.5g in a 24 hr period
7. History of significant gastrointestinal impairment, as judged by the Investigator, that would significantly affect the absorption of cediranib, including the ability to swallow the tablet whole
8. Patient with a history of poorly controlled hypertension with resting blood pressure > 150/100mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy, or patients who are requiring maximal doses of calcium channel blockers to stabilise blood pressure.
9. Any evidence of severe or uncontrolled diseases (eg, unstable or uncompensated respiratory, cardiac, hepatic or renal disease)
10. Unresolved toxicity > CTCAE grade 1 from previous anti-cancer therapy (including radiotherapy) except alopecia (if applicable)
11. Mean QTc with Bazetts correction >470msec in screening ECG or history of familial, long QT syndrome
12. Significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in previous 4 weeks)
13. Recent (<14 days) major thoracic or abdominal surgery or brain biopsy. Recent craniotomy(<28 days) prior to entry into the study, or a surgical incision that is not fully healed.
14. Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication
15. Known hypersensitivity to cediranib or any of its excipients
16. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease free for 2 years and they have tissue diagnosis of the target lesion.
17. Known infection with hepatitis B or C or HIV
18. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site)
19. Previous enrolment or randomisation of treatment in the present study.
20. Treatment with an investigational drug within 30 days prior to the first dose of cediranib
21. Other concomitant anti-cancer therapy except steroids
22. Previous anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) therapy
23. Patients with evidence of any intratumoral or peritumoral haemorrhage deemed significant by the treating physician
24. Patients who have received any form of cranial radiation within 3 months prior to study entry.
25. Known hypersensitivity to lomustine or any of its excipients
26. Patients with a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO)
27. Patients who have progressed within 3 months of standard therapy with cranial radiation
28. Patients receiving radiosurgery or brachytherapy within 3 months prior to enrolment
29. Patients with Celiac Disease
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome variable is PFS. The end of study is defined as the date when 270 subjects have died. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| cediranib monotherapy arm will be open label, two arms containing lomustine will be double-blinded |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of study is defined as the date when 270 subjects have died |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
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