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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 3, 2018
Sponsor:
Collaborators:
Oslo University Hospital
St. Olavs Hospital
University Hospital of North Norway
University of Bergen
University of Bonn
University of Oslo
Information provided by (Responsible Party):
Haukeland University Hospital

Tracking Information
First Submitted Date  ICMJE August 21, 2018
First Posted Date  ICMJE August 22, 2018
Last Update Posted Date September 3, 2018
Actual Study Start Date  ICMJE August 30, 2018
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2018)
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03643549 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2018)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bortezomib and Temozolomide in Recurrent Glioblastoma With Unmethylated MGMT Promoter (BORTEM-17)
Official Title  ICMJE Bortezomib Sensitization of Recurrent Glioblastoma With Unmethylated MGMT Promoter to Temozolomide Phase 1B/II Study
Brief Summary 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

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: Bortezomib and Temozolomide Phase IB
  • Drug: Bortezomib and Temozolomide Phase II
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 21, 2018)
63
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 31, 2023
Estimated Primary Completion Date August 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • 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
  • 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
  • Stable or decreasing steroid dose during the two weeks before study entry
  • 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 PCV 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.
  • Concurrent inducers of CYP450 3A4 (e.g., enzyme-inducing anti-epileptic drugs [EIAED])
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dorota Goplen, MD, PhD +47 55974019 dgop@helse-bergen.no
Contact: Martha E Chekenya, PhD, Dr. Philos +47 55586380 martha.enger@uib.no
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03643549
Other Study ID Numbers  ICMJE BORTEM-17
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Haukeland University Hospital
Study Sponsor  ICMJE Haukeland University Hospital
Collaborators  ICMJE
  • Oslo University Hospital
  • St. Olavs Hospital
  • University Hospital of North Norway
  • University of Bergen
  • University of Bonn
  • University of Oslo
Investigators  ICMJE
Principal Investigator: Dorota Goplen, MD, PhD Haukeland University Hospital
PRS Account Haukeland University Hospital
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP