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

  • STATUS
    Recruiting
  • End date
    Aug 30, 2023
  • participants needed
    63
  • sponsor
    Haukeland University Hospital
Updated on 4 September 2021
platelet count
corticosteroids
karnofsky performance status
blood transfusion
temozolomide
recurrent glioblastoma
recurrent tumor

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.

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 tumours 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.

Details
Condition Glioblastoma Multiforme, Glioblastoma multiforme, glioblastoma
Treatment Bortezomib and Temozolomide Phase IB, Bortezomib and Temozolomide Phase II
Clinical Study IdentifierNCT03643549
SponsorHaukeland University Hospital
Last Modified on4 September 2021

Eligibility

Yes No Not Sure

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
WBC 3,000/mm^3
Karnofsky performance status 70
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
Stable or reduced doses of corticosteroids for at least 1 week prior to enrolment
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])
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