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

• ClinicalTrials.gov Identifier: NCT03643549
• Recruitment Status: Recruiting
• First Posted: August 22, 2018
• Last Update Posted: August 27, 2021
• Sponsor: Haukeland University Hospital
• 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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma	Drug: Bortezomib and Temozolomide Phase IB; Drug: Bortezomib and Temozolomide Phase II	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 63 participants
• Allocation: N/A
• 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
• 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: December 31, 2022
• Estimated Study Completion Date: August 30, 2023

Arms and Interventions

Arm

Intervention/treatment

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

Outcome Measures

Primary Outcome Measures :

1. Bortezomib-Temozolomide Maximum tolerated dose [ Time Frame: 6 months ]
   En intra- and inter-patient dose escalation period of TMZ administered after Bortezomib
2. Overall survival [ Time Frame: 1 year ]
   Overall survival at 1 year
3. Progression free survival [ Time Frame: 6 months ]
   Progression free survival at 6 months
4. Time to progression [ Time Frame: 4 years ]
   Median time

Secondary Outcome Measures :

1. 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
2. Tumour responses [ Time Frame: 4 years ]
   Assessed by contrast enhanced MRI according to RANO criteria
3. Clinical response [ Time Frame: 4 years ]
   Assessment of the neurologic status according to NANO criteria
4. Toxicity assessment [ Time Frame: 4 years ]
   SAE, all grades hematologic and non hematologic toxicity

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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])

Contacts and Locations

Contacts

Contact: Dorota Goplen, MD, PhD; +47 55974019; dgop@helse-bergen.no

Contact: Martha E Chekenya, PhD, Dr. Philos; +47 55586380; martha.enger@uib.no

Locations

Norway

Haukeland University Hospital; Recruiting

Bergen, Norway, 5021

Contact: Dorota Goplen, MD, PhD +4755974019 dgop@helse-bergen.no

Contact: Jorunn Brekke, MD +4755970986 joub@helse-bergen.no

Oslo University Hospital; Recruiting

Oslo, Norway, 0424

Contact: Petter Brandal, MD pebra@ous-hf.no

Sponsors and Collaborators

Haukeland University Hospital

Oslo University Hospital

St. Olavs Hospital

University Hospital of North Norway

University of Bergen

University of Bonn

University of Oslo

Investigators

• Principal Investigator: Dorota Goplen, MD, PhD; Haukeland University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rahman MA, Brekke J, Arnesen V, Hannisdal MH, Navarro AG, Waha A, Herfindal L, Rygh CB, Bratland E, Brandal P, Haasz J, Oltedal L, Miletic H, Lundervold A, Lie SA, Goplen D, Chekenya M. Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study. Immun Inflamm Dis. 2020 Sep;8(3):342-359. doi: 10.1002/iid3.315. Epub 2020 Jun 24.

• Responsible Party: Haukeland University Hospital
• ClinicalTrials.gov Identifier: NCT03643549
• Other Study ID Numbers: 2017/2084
• First Posted: August 22, 2018
• Last Update Posted: August 27, 2021
• Last Verified: August 2021

• 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

Keywords provided by Haukeland University Hospital:

Temozolomide; Bortezomib; Recurrent disease

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Bortezomib; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents