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

Sponsor

Haukeland University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03643549

Collaborator

Oslo University Hospital (Other), St. Olavs Hospital (Other), University Hospital of North Norway (Other), University of Bergen (Other), University of Bonn (Other), University of Oslo (Other)

Enrollment

Locations

Arm

Anticipated Duration (Months)

31.5

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

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

Anticipated 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 managementBotezomib 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 :

Aug 30, 2018

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Aug 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

Arm

Intervention/Treatment

Experimental: Bortezomib and Temozolomide

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

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

Secondary Outcome Measures

Biomarkers of treatment response [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 [4 years]
Assessed by contrast enhanced MRI according to RANO criteria
Clinical response [4 years]
Assessment of the neurologic status according to NANO criteria
Toxicity assessment [4 years]
SAE, all grades hematologic and non hematologic toxicity

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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])