Bortezomib and Temozolomide in Recurrent Glioblastoma With Unmethylated MGMT Promoter (BORTEM-17) (BORTEM-17)
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|ClinicalTrials.gov Identifier: NCT03643549|
Recruitment Status : Recruiting
First Posted : August 22, 2018
Last Update Posted : September 4, 2018
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma||Drug: Bortezomib and Temozolomide Phase IB Drug: Bortezomib and Temozolomide Phase II||Phase 1 Phase 2|
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.
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||63 participants|
|Intervention Model:||Sequential Assignment|
|Intervention 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)|
|Official Title:||Bortezomib Sensitization of Recurrent Glioblastoma With Unmethylated MGMT Promoter to Temozolomide Phase 1B/II Study|
|Actual Study Start Date :||August 30, 2018|
|Estimated Primary Completion Date :||August 31, 2021|
|Estimated Study Completion Date :||August 31, 2023|
Experimental: Bortezomib and Temozolomide
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
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.
Drug: Bortezomib and Temozolomide Phase II
The patientes will be treated with the maximum recommended starting dose of Temozolomide and Bortezomib established in the IB phase of the study
- Bortezomib-Temozolomide Maximum tolerated dose [ Time Frame: 6 months ]En intra- and inter-patient dose escalation period of TMZ administered after Bortezomib
- Overall survival [ Time Frame: 1 year ]Overall survival at 1 year
- Progression free survival [ Time Frame: 6 months ]Progression free survival at 6 months
- Time to progression [ Time Frame: 4 years ]Median time
- Biomarkers of treatment response [ Time Frame: 4 years ]Identification of novel tumor biomarkers by determining physiological, molecular and biochemical changes in blood and tumor tissue that correlate with treatment responses
- Tumour responses [ Time Frame: 4 years ]Assessed by contrast enhanced MRI according to RANO criteria
- Clinical response [ Time Frame: 4 years ]Assessment of the neurologic status according to NANO criteria
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03643549
|Contact: Dorota Goplen, MD, PhD||+47 firstname.lastname@example.org|
|Contact: Martha E Chekenya, PhD, Dr. Philos||+47 email@example.com|
|Principal Investigator:||Dorota Goplen, MD, PhD||Haukeland University Hospital|