Bortezomib and Temozolomide in Recurrent Glioblastoma With Unmethylated MGMT Promoter (BORTEM-17)

Study Overview
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Brief Summary
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This phase IB/II trial is designed to investigate the safety and survival benefits for patients with recurrent glioblastoma with unmethylated MGMT promoter treated with Bortezomib and Temozolomide in a specific schedule.

Detailed Description
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Patients harbouring tumours with functional O6 methylguanine DNA methyltransferase (MGMT) DNA repair enzyme efficiently repair the DNA damage inflicted by Temozolomide and gain limited benefit from this chemotherapy. Bortezomib depletes the MGMT enzyme, restoring the tumour´s susceptibility to Temozolomide, if the chemotherapy is administered in the precise schedule when the MGMT enzyme is depleted. Additionally, Bortezomib inhibits the growth of tumour cells by blocking autophagy flux. Temozolomide causes genotoxic stress in cancer cells that in turn respond by inducing protective processes such as autophagy. If both autophagy and MGMT DNA repair enzyme are blocked a priori, the efficacy of Temozolomide will be enhanced. Thus, pre-treating the tumour with Bortezomib prior to administration of Temozolomide leads to DNA repair enzyme depletion and blockade of autophagy-induced survival signals. The combined effect will sensitize the tumour to therapy, improve chemotherapy efficacy and prolong patient survival outcomes. Hypothesis: Pretreatment with Bortezomib administered prior to Temozolomide will sensitize recurrent GBM with unmethylated MGMT promoter to standard TMZ in palliative setting. Objective: Assessment of safety and tolerability of Bortezomib administered with Temozolomide. Determining the optimal dose of TMZ, when administered as combination therapy Estimate the 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. Key secondary objectives Tumour response to the therapy assessed by RANO and NANO criteria Determine physiological, molecular and biochemical changes in blood and tumour tissue that correlate with treatment responses.

Official Title
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Bortezomib Sensitization of Recurrent Glioblastoma With Unmethylated MGMT Promoter to Temozolomide Phase 1B/II Study

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: Bortezomib and Temozolomide Phase IB
* Drug: Bortezomib and Temozolomide Phase II


Participation Criteria
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Eligibility Criteria
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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])

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Botezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with per oral Temozolomide at three dose levels: 150 mg/m2, 175 mg/m2 and 200mg/m2 5 days/week every 4 weeks starting on day 3 until disease progression and/or unacceptable toxicity. Study group will be compared to historical controls on conventional management
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib and Temozolomide<br>Botezomib 1.3 mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with per oral Temozolomide at three dose levels: 150 mg/m2, 175 mg/m2 and 200mg/m2 5 days/week every 4 weeks starting on day 3. | Drug: Bortezomib and Temozolomide Phase IB<br>* In the Phase IB of the study the following dose escalation of TMZ will be performed: The first cohort of 3 patients will receive 150 mg/m2 of IMP (TMZ) for 5 days q4w. If one patient in this cohort develops a dose limiting toxicity, another cohort of 3 patients will be treated at the same dose level until 2 or more patients in the group of 3-6 develop DLT.<br>Drug: Bortezomib and Temozolomide Phase II<br>* The patientes will be treated with the maximum recommended starting dose of Temozolomide and Bortezomib established in the IB phase of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bortezomib-Temozolomide Maximum tolerated dose | En intra- and inter-patient dose escalation period of TMZ administered after Bortezomib | 6 months | 
| Overall survival | Overall survival at 1 year | 1 year | 
| Progression free survival | Progression free survival at 6 months | 6 months | 
| Time to progression | Median time | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of treatment response | Identification of novel tumor biomarkers by determining physiological, molecular and biochemical changes in blood and tumor tissue that correlate with treatment responses | 4 years | 
| Tumour responses | Assessed by contrast enhanced MRI according to RANO criteria | 4 years | 
| Clinical response | Assessment of the neurologic status according to NANO criteria | 4 years | 
| Toxicity assessment | SAE, all grades hematologic and non hematologic toxicity | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Temozolomide, Bortezomib, Recurrent disease