E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018336 |
E.1.2 | Term | Glioblastoma |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of addition of continuous multiple line
bevacizumab treatment to lomustine in 2nd-line followed by standard of
care (SOC) in 3rd-line and beyond compared to addition of bevacizumabplacebo,
as measured by overall survival (OS) from randomisation at
first progression of disease (PD1). |
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E.2.2 | Secondary objectives of the trial |
To assess:
• overall survival as measured from randomization at PD1.
• progression free survival from randomization at PD1, to 2nd PD (PD2) (PFS2), and to 3rd PD (PD3) (PFS3).
• response rates (RRs), disease control rates (DCRs), and durations of response at PD2 and PD3.
• the safety of bevacizumab treatment across multiple lines of treatment and from randomization at PD1.
• HRQoL, neurocognitive function (NCF) and resource utilization
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Are currently enrolled in Study MO28347 and have provided additional consent following amendment 6 to the protocol, which changed the
study from a Phase IIIb to a Phase II study
• Age ≥ 18 years .
• Karnofsky performance status (KPS) ≥ 60.
• Newly diagnosed, histologically confirmed glioblastoma not previously treated with chemotherypy or radiotherapy
• If female and not postmenopausal (< 12 months of amenorrhea) or
surgically sterile, must agree to use a highly effective contraceptive
method during the treatment period and for at least 6 months after the
last dose of study drug
• Mandatory tissue collection during pre-study surgery or biopsy for
• Craniotomy or intracranial biopsy site must be adequately healed. Study treatment should be initiated > 28 days following the last surgical
procedure.
Principal eligibility criteria at the time of randomisation (following PD1):
• Documented disease progression (PD1)
• Eligibility for 2nd-line treatment with lomustine and bevacizumab as
investigational medicinal products.
• Patients for whom operation or re-operation is indicated before 2ndline
starts, tissue submission is mandatory
• Eastern Cooperative Oncology Group (ECOG) performance status is 0-2
when starting 2nd-line treatment
• Bevacizumab was well tolerated and treatment interruption lasted not
more than 60 days
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E.4 | Principal exclusion criteria |
• Any prior chemotherapy for GBM and low grade astrocytomas.
• Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field.
• Prior or current anti-angiogenic treatment (i.e. anti-VEGF or VEGFR therapies or tyrosine kinase inhibitors).
•Treatment with any other investigational drug within 28 days or 2
investigational agent half-lives (whichever is longer) prior to first study
treatment
• Inadequate hematological, renal or liver function
• Inadequately controlled hypertension
• Prior history of gastrointestinal perforation or abscess
• Clinically significant cardiovascular disease, NYHA >/= Grade II
congestive heart failure, or serious cardiac arrhythmia uncontrolled by
medication or potentially interfering with protocol treatment
• History or evidence of central nervous system disease unrelated to
cancer unless adequately treated with standard medical therapy
• History or evidence of inherited bleeding diathesis or significant
coagulopathy at risk of bleeding
• Serious non-healing wound, active ulcer, or untreated bone fracture
• Known hypersensitivity to any component of Avastin/placebo or any of
the study drugs
• Active infection requiring intravenous antibiotics at start of study
treatment
• Other malignancy within 5 years prior to study enrollment, except for
carcinoma in situ of the cervix, basal or squamous cell skin cancer,
localized prostate cancer or ductal carcinoma in situ treated with
curative intent
• Pregnant or lactating women
• Participation in any other study
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When 130 events have been observed |
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E.5.2 | Secondary end point(s) |
- 2nd and 3rd line progression free survival (PFS)
- Response, duration of response and disease control rates in 2nd and 3rd line
- Safety
- Neurocognitive function, Health Related QoL, resource utilization |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the time of the primary endpoint (when 130 events have been observed) |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Health related Quality of Life, Neurocognitive function |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 53 |
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 | No |
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 |
Austria |
Bulgaria |
Croatia |
Estonia |
France |
Greece |
Italy |
Latvia |
Portugal |
Romania |
Spain |
Sweden |
Turkey |
United Kingdom |
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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
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The end of the study is defined as the date when the LPLV occurs. LPLV is planned 30 days after the 130th OS event is reported which is
estimated approximately 36 months after the first patient is enrolled. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |