Combining Bortezomib and Temozolomide for Recurrent Glioblastoma

Bortezomib Sensitization of Recurrent Grade-4 Glioma With Unmethylated MGMT Promoter to Temozolomide Phase 1B/II Study

This study is testing if giving Bortezomib before Temozolomide can help people with recurrent glioblastoma live longer and feel better by making the chemotherapy work more effectively.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 63 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Haukeland University Hospital (Academic / other)
• Drugs / interventions: bevacizumab, chemotherapy
• Locations: 2 sites (Bergen and 1 other locations)
• Trial ID: NCT03643549 on ClinicalTrials.gov

What this trial studies

This trial investigates the safety and survival benefits of using Bortezomib in combination with Temozolomide for patients with recurrent grade-4 glioblastoma that has an unmethylated MGMT promoter. The approach aims to deplete the MGMT enzyme, which repairs DNA damage caused by Temozolomide, thereby enhancing the chemotherapy's effectiveness. By administering Bortezomib prior to Temozolomide, the study seeks to block protective processes in tumor cells, potentially improving patient outcomes. The trial will assess the optimal dosing, safety, and overall survival rates of this combination therapy.

Who should consider this trial

Good fit: Ideal candidates include patients with recurrent glioblastoma who have an unmethylated MGMT promoter and meet specific health criteria.

Not a fit: Patients with glioblastoma that have a methylated MGMT promoter or those with a life expectancy of less than 8 weeks may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve survival rates for patients with recurrent glioblastoma.

How similar studies have performed: Other studies have shown promise in using similar combination therapies, but this specific approach is novel in targeting the MGMT enzyme in recurrent glioblastoma.

Eligibility criteria

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 \[EIAED\])

Where this trial is running

Bergen and 1 other locations

• Haukeland University Hospital — Bergen, Norway (Recruiting)
• Oslo University Hospital — Oslo, Norway (Recruiting)

Study contacts

• Principal investigator: Dorota Goplen, MD, PhD — Haukeland University Hospital
• Study coordinator: Dorota Goplen, MD, PhD

Conditions Glioblastoma; Temozolomide; Bortezomib; Recurrent disease