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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
Sponsor:
Information provided by (Responsible Party):
University of Chicago

Brief Summary:
We hypothesize that ACZ can be safely administered concomitantly with TMZ in patients with malignant glioma and that this regimen improves patient survival without increasing toxicity to an unacceptable level. Information gathered from this study will contribute towards the development of a future larger phase II study in these tumors.

Condition or disease Intervention/treatment Phase
Malignant Glioma of Brain Drug: Acetazolamide Drug: Temozolomide Phase 1

Detailed Description:

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 [1]. 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 [2]. 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.

Secondary Objectives:

  1. To describe objective response rate (ORR), progression free survival (PFS) and overall survival (OS).
  2. 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.
  3. 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)
Primary Purpose: Treatment
Official Title: A Phase I Study of Safety and Tolerability of Acetazolamide With Temozolomide in Adults With Newly Diagnosed Malignant Glioma
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
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.
Drug: Acetazolamide
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:
  • Diamox
  • Diamox Sequels
Drug: Temozolomide
Patients will receive daily oral ACZ concomitant with TMZ. ACZ will be started on the day of TMZ initiation.
Other Name: Temodar



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.).

  2. Time until progression free survival (PFS) [ Time Frame: 6 months ]
  3. 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 ]
  4. 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.



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

Inclusion Criteria:

  • Histologically proven, newly diagnosed WHO grade III or IV glioma.
  • Patients are eligible if they had a prior low grade glioma and there is subsequent histological evidence of a diagnosis of grade III or IV tumor.
  • Patients must be receiving TMZ as part of their treatment regimen.
  • Patients must be ECOG performance status ≤1 or Karnofsky performance ≥60% (see appendix A).
  • Normal organ activity, which includes adequate bone marrow function as defined by the following laboratory values:

    • Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/ L
    • Platelets ≥ 80 x 109 / L
    • Hemoglobin ≥ 8.0 g / dL
  • Age ≥18 years. Because of the risk of adverse events in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  • Renal function (creatinine level within normal institutional limit, or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine level above institutional normal).
  • Liver function (AST/ALT <2.5 X institutional upper limit of normal, Total bilirubin ≤ 1.5 times ULN, INR within 1.5 times ULN (or if receiving anticoagulant therapy an INR of ≤ 3.0 is allowed with concomitant increase in PT or an aPTT ≤ 2.5 × control).
  • Women of childbearing potential must have a negative pregnancy test within 30 days of registration.
  • Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Prior invasive malignancy that is not low-grade glioma (except non-melanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease free and off therapy for that disease for a minimum of 3 years.
  • Active systemic infection requiring treatment, including any HIV infection or toxoplasmosis.
  • Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration.
  • Systemic corticosteroid therapy, >2 mg of dexamethasone daily (or equivalent) at study enrollment.
  • Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration that may interfere with the interpretation of study results and in the judgment of the investigator would make the patient inappropriate for entry into this study.
  • Pregnant women are excluded from this study, where pregnancy is confirmed by a positive serum beta-hCG laboratory test. Breast-feeding should be discontinued.

Information from the National Library of Medicine

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


Contacts
Contact: Bakhtiar Yamini, M.D. 7737022123 byamini@surgery.bsd.uchicago.edu

Locations
United States, Illinois
University of Chicago Medical Center Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Bakhtiar Yamini, MD       byamini@surgery.bsd.uchicago.edu   
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Bakhtiar Yamini, MD University of Chicago

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT03011671     History of Changes
Other Study ID Numbers: IRB16-0767
First Posted: January 5, 2017    Key Record Dates
Last Update Posted: February 7, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Chicago:
Malignant Glioma of Brain
Acetazolamide
Temozolomide

Additional relevant MeSH terms:
Anticonvulsants
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Acetazolamide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Diuretics
Natriuretic Agents
Physiological Effects of Drugs