Bortezomib and Temozolomide in Recurrent Grade-4 Glioma Unmethylated MGMT Promoter (BORTEM-17)

Inclusion Criteria:

* Life expectancy \> 8 weeks
* Histologically confirmed intracranial glioblastoma (GBM), with MGMT unmethylated promoter
* Must submit an unstained paraffin block and/ or cryopreserved tumour tissue from surgical procedure
* Radiologically (MRI) confirmed tumour relapse/progression ≥ 12 weeks since completed radiotherapy
* Measurable recurrent tumor
* Tumor not available for radio-surgery
* If previously treated with gammaknife, at least one evaluable lesion outside the irradiated area is required, unless the time after the radiosurgery is 12 weeks or more
* Written informed consent for study participation and tumour, blood sample collection obtained before performance of any study related procedure.
* Karnofsky performance status ≥ 70
* WBC ≥ 3,000/mm\^3
* ANC ≥ 1,500/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10 g/dL (transfusion allowed)
* Bilirubin \< 2.5 times upper limit of normal (ULN)
* serum aspartate aminotransferase (AST) \< 2.5 times ULN
* Estimated GFR ≥ 60 mL/minute
* Serum sodium \> 130 mmol/L
* Serum potassium level within normal limit
* Stable or reduced doses of corticosteroids for at least 1 week prior to enrolment
* Negative pregnancy test no longer than 14 days prior to enrollment
* Fertile patients and female partners with child bearing potential of male patients must use adequate contraception
* Patients on EIAED must be transitioned to non-EAIED for ≥ 2 weeks
* Unfractionated and/or low molecular weight heparin allowed
* Patients previously treated with neurosurgery er eligible for the study

Exclusion Criteria:

* Hypersensitivity to Bortezomib, boron, or mannitol
* Any contraindications for use of temozolomide
* Peripheral neuropathy ≥ grade 2
* Previous treatment with bevacizumab or lomustine alone or as a combination therapy for ralapsed glioblastoma (PCV as primary treatment of low grade glioma, before development of glioblastoma, is allowed)
* Myocardial infarction within the past 6 months
* NYHA class III or IV heart failure
* Uncontrolled angina
* Severe uncontrolled ventricular arrhythmias
* Electrocardiographic evidence of acute ischemia or active conduction system abnormalities
* Known heart failure
* Serious medical or psychiatric illness that would interfere with the 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
* 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 the drug metabolism
* Viral hepatitis (HBV surface antigen positive) or active hepatitis C infection
* Other investigational drugs must be stopped at least 12 weeks prior to therapy or treatment failure under other experimental therapy must be confirmed before study entry. If progression during other experimental therapy is confirmed, the time interval between previous treatment and BORTEM-17 may be reduced to 4 weeks
* Concurrent inducers of CYP450 3A4 (e.g., enzyme-inducing anti-epileptic drugs \[EIAED\])