Phase I Study of Safety and Tolerability of Acetazolamide With Temozolomide
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|ClinicalTrials.gov Identifier: NCT03011671|
Recruitment Status : Not yet recruiting
First Posted : January 5, 2017
Last Update Posted : February 7, 2018
|Condition or disease||Intervention/treatment||Phase|
|Malignant Glioma of Brain||Drug: Acetazolamide Drug: Temozolomide||Phase 1|
Malignant gliomas are a diverse group of tumors that encompass WHO grade III and WHO grade IV, glioblastoma (GBM), tumors. Alkylating chemotherapy is central to the management of these tumors and temozolomide (TMZ) is now the most commonly used anti-glioma chemotherapeutic . Standard treatment for newly diagnosed malignant glioma involves concomitant TMZ and ionizing radiation (IR). Despite its routine use, many patients experience minimal benefit from the addition of TMZ . Given that no new chemotherapeutics have been approved for GBM in over a decade, identification of strategies to enhance the efficacy of TMZ is important. In preliminary work, we identified the proto-oncogene, Bcl-3, as a biomarker in glioma that can predict response to TMZ. In examining the mechanism by which Bcl-3 promotes resistance to therapy, we identified carbonic anhydrase II (CAII) as a unique factor that is both Bcl-3-dependent and induced by TMZ. CAII is potently inhibited by the oral CA inhibitor, acetazolamide (ACZ, Diamox), an FDA-approved agent used for a variety of medical conditions seen in patients with glioma including epilepsy and raised intracranial pressure. Importantly, using patient-derived GBM cells and xenografts we find that ACZ sensitizes GBM to TMZ. Specifically, our pre-clinical studies show that daily ACZ given in combination with TMZ and extended for 21 days after TMZ initiation significantly prolongs survival of animals bearing GBM xenografts compared to TMZ alone.
Primary Objective: To determine the safety, tolerability and adverse event profile of adding acetazolamide to temozolomide in patients with newly diagnosed malignant glioma.
- To describe objective response rate (ORR), progression free survival (PFS) and overall survival (OS).
- To determine the feasibility of accrual, and adequacy of eligibility criteria, by defining the proportion of patients enrolled from the eligible cases of malignant glioma presented at the weekly multidisciplinary Neuro-oncology tumor board at the University of Chicago Medical Center.
- To evaluate Bcl-3 expression level within each tumor and preliminarily examine the ability of Bcl-3 to predict response to TMZ and the efficacy of adding ACZ.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Safety and Tolerability of Acetazolamide With Temozolomide in Adults With Newly Diagnosed Malignant Glioma|
|Anticipated Study Start Date :||December 2018|
|Estimated Primary Completion Date :||February 2020|
|Estimated Study Completion Date :||March 2020|
Experimental: Acetazolamide with Temozolomide
Patients will receive daily oral ACZ concomitant with TMZ. ACZ will be initiated at 250 mg twice a day (BID) and then escalated to 500 mg BID. ACZ will be started on the day of TMZ initiation. During the concomitant TMZ/IR phase, ACZ will be continued throughout the course of TMZ and for an extra 10 days after TMZ cessation. During each maintenance cycle, ACZ will be given during TMZ treatment (Days 1-5) and continued for a total of 21 days.
ACZ will be initiated at 250 mg twice a day (BID) and then escalated to 500 mg BID. ACZ will be started on the day of TMZ initiation.
Other Names:Drug: Temozolomide
Patients will receive daily oral ACZ concomitant with TMZ. ACZ will be started on the day of TMZ initiation.
Other Name: Temodar
- Number of participants with adverse events [ Time Frame: 28 Days ]To determine the safety, tolerability and adverse event profile of adding acetazolamide to temozolomide in patients with newly diagnosed malignant glioma.
- Measure objective response rate (ORR); change in tumor size [ Time Frame: 6 months ]ORR will be determined at 6 months and is based on the change in tumor size (as determined by Response Assessment in Neuro-Oncology Criteria (RANO) criteria) at the indicated time relative to the pre-treatment scan. RANO criteria will also be used to define disease status (CR, PR, etc.).
- Time until progression free survival (PFS) [ Time Frame: 6 months ]
- Time until overall survival (OS) [ Time Frame: From start date of therapy to the date of death from any cause, whichever may come first, assessed up to 100 months ]
- Analysis of formalin fixed paraffin embedded surgical specimens. [ Time Frame: Through study completion an average of one year ]Bcl-3 expression will be determined by an independent neuro-pathologist by immunohistochemical analysis of formalin fixed paraffin embedded (FFPE) surgical specimens. This is to evaluate Bcl-3 expression level within each tumor and preliminarily examine the ability of Bcl-3 to predict response to TMZ and the efficacy of adding ACZ.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03011671
|Contact: Bakhtiar Yamini, M.D.||email@example.com|
|United States, Illinois|
|University of Chicago Medical Center||Not yet recruiting|
|Chicago, Illinois, United States, 60637|
|Contact: Bakhtiar Yamini, MD firstname.lastname@example.org|
|Principal Investigator:||Bakhtiar Yamini, MD||University of Chicago|