E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
recurrent or progressed WHO grade IV intracranial glioblastoma |
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E.1.1.1 | Medical condition in easily understood language |
recurrent or progressed WHO grade IV intracranial glioblastoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
Phase IB: Assessment of safety and tolerability of Bortezomib administered with Temozolomide. Determination of the optimal dose of TMZ and BTZ given as combination therapy
Phase II: Assessment of efficacy of Bortezomib administered with Temozolomide.
Estimation of the median progression free survival (PFS) and overall survival (OS) of patients with recurrent or progressed glioblastoma after pre-treatment with Bortezomib prior to combination with Temozolomide as well as progression free rate at 6 months
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives
• Determine physiological, molecular and biochemical changes in blood and tumour tissue that correlate with treatment responses:
- Changes in natural killer cell phenotype and function
- Changes in autophagy flux
-Abrogation of 26S proteasome activity
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All of the following conditions must apply to the prospective patient at screening prior to receiving study agent (e.g.):
Histologically confirmed recurrent or progressed WHO grade IV intracranial glioblastoma (GBM), MRI evidence of recurrence within 14 days prior to enrolment
Unmethylated MGMT promoter characterised from tissue obtained at operation
Must submit an unstained paraffin block and cryopreserved tumour tissue from surgical procedure
Must be >- 18 years old, with a life expectancy > 8 weeks
Cranial MRI or contrast CT scan showing tumour relapse ≥ 12 weeks since radiation treatment
Measurable recurrent tumour
Tumour not available for radiosurgery
Written informed consent for study participation and tumour, blood sample collection obtained before performance of any study related procedure, and not part of normal medical care.
Karnofsky performance status ≥ 70%
WBC ≥ 3,000/mm^3
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Prothrombin time/international normalized ratio (PT INR) < 1.4.
Haemoglobin ≥ 10 g/dL (transfusion allowed)
Bilirubin < 2.5 times upper limit of normal (ULN)
Serum aspartate aminotransferase (AST); < 2.5 times ULN
Adequate hepatic function: serum bilirubin ≤ 1.5 x ULN, AST, ALT and alkaline phosphatase ≤ 2.5 ULN,
Serum potassium within normal limit
Serum creatinine < 1.5 mg/dL
Estimated GFR ≥ 60
Stable doses of corticosteroids for at least 1 week prior to enrolment, but analgesics and other drugs to treat symptoms or prevent complications allowed
Patients receiving EIAED must be transitioned to non-EIAED at least 2 weeks before study inclusion
Unfractionated and/or low molecular weight heparin is allowed
Other investigational drugs must be discontinued at least 12 weeks prior to study entry
Eligibility for standard therapy with Temozolomid as 5-days treatment q4w. |
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E.4 | Principal exclusion criteria |
- hypersensitivity to Bortezomib, boron, or mannitol
- Peripheral neuropathy ≥ grade 2
- Myocardial infarction within the past 6 months
- NYHA class III or IV heart failure
- Uncontrolled angina
- Severe uncontrolled ventricular arrhythmias
- LVEF ≤ 45 % at echocardiography
- Electrocardiographic evidence of acute ischemia or active conduction system abnormalities
- serious medical or psychiatric illness that would interfere with study participation including, but not limited to, any of the following:
- Ongoing or active infection requiring IV antibiotics
- Psychiatric illness and/or social situations that would limit compliance with study requirements
- Ongoing, uncontrolled infection requiring IV antibiotics
- Disorders associated with a significant immunocompromised state (e.g., HIV, systemic lupus erythematosus)
- history of stroke within the past 6 months
- other malignancy within the past 3 years except completely resected basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy (i.e., cervical cancer), or low-risk prostate cancer after curative therapy
- 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
- disease that will obscure toxicity or dangerously alter drug metabolism
- viral hepatitis (HBV surface antigen positive) or active hepatitis C infection
- concurrent investigational drugs (chemotherapy) must be stopped at least 4 weeks prior to therapy.
- concurrent inducers of CYP450 3A4 (e.g., enzyme-inducing anti-epileptic drugs [EIAED] e.g. phenytoin, fosphenytoin, carbamazepine, phenobarbital, or primidone)
- Another ongoing experimental therapy
- Any contraindications for use of Temozolomid |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Assessment of efficacy of Temozolomide administered together with Bortezomib in recurrent glioblastoma. Overall survival (OS) at 1 year [from operation date histologically diagnosing GBM to date of death]
• Assessment of safety and tolerability of Bortezomib administered with Temozolomide
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Toxicity assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Progression free survival at 6 months [from date of enrolment to date of progression or death]
- Time to progression (TTP)
- [ from date of enrolment to date of date of progression]
- Tumour response as assessed by contrast enhanced MRI using RANO criteria and neurological exam
- [Time Frame: MRI at start of treatment and every 8th week, neurologic exam every 4 weeks] After completion of treatment, follow up MRI will be performed at 8th week, then every 8th week until endpoint evaluation at 6 months. If objective responses are observed, then MRI every 12 weeks until the 1-year endpoint. Correspondingly, Neurologic exam and KPS at same time points. Patients responding to the therapy without treatment related toxicity rendering its discontinuation will receive therapy until progression and/or consent withdrawal.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
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) | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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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 | |
E.8.9.1 | In the Member State concerned days | |