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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 : April 25, 2018
Sponsor:
Information provided by (Responsible Party):
University of Chicago

Brief Summary:

This is a Phase I study that examines the rate of dose limiting side effects in patients with malignant astrocytoma treated with combination acetazolamide (ACZ) and temazolomide (TMZ). Eligible patients must have histologically proven newly diagnosed, O6-methylguanine-DNA methyltransferase (MGMT) methylated WHO grade III or IV astrocytoma and be planning to undergo treatment with standard adjuvant TMZ (after completing treatment with TMZ and ionizing radiation (IR)).

During this study, patients will receive daily oral ACZ with TMZ. During each cycle, ACZ will be started on the day of TMZ initiation and continued for a total of 21 days.


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

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 MGMT Promoter-Methylated 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


Arm Intervention/treatment
Experimental: Acetazolamide with Temozolomide
Subjects will receive daily ACZ together with TMZ in 28 day cycles for up to 6 cycles if they do not experience either disease worsening or unacceptable side effects.
Drug: Acetazolamide
ACZ will be given at an initial dose of 250 mg twice a day (BID) and then escalated to 500 mg BID after 1 week. ACZ will be given on days 1-21 of each cycle.
Other Names:
  • Diamox
  • Diamox Sequels

Drug: Temozolomide
For cycle 1 of the maintenance phase, TMZ will administered at 150 mg/m2 on days 1- 5 followed by 23 days with no drug. For cycles 2- 6, TMZ can be increased to 200 mg/m2 at the discretion of the treating investigator.
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, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven, newly diagnosed WHO grade III or IV astrocytoma that has a methylated MGMT promoter as assessed by the standardized institutional analysis.
  • Patients are eligible if they had a prior low grade astrocytoma and there is subsequent histological evidence of a diagnosis of grade III or IV tumor.
  • Patients must be receiving TMZ as part of their standard adjuvant treatment regimen following treatment with TMZ and Radiation.
  • Patients must have a Karnofsky performance ≥ 60%.
  • Normal organ function as follows:

    • Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/ L
    • Platelets ≥ 100 x 10^9 / L
    • Hemoglobin ≥ 8.0 g / dL
  • Age 18 years or older.
  • Kidney 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 (ULN), 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 able to become pregnant 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, >8 mg of dexamethasone daily (or equivalent) at study enrollment.
  • Pregnant women are excluded from this study, where pregnancy is confirmed by a positive serum beta-hCG laboratory test. Breast-feeding should be discontinued.
  • Hypersensitivity to acetazolamide or sulfonamides.

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. 773-702-2123 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: April 25, 2018
Last Verified: April 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:
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
Anticonvulsants
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Diuretics
Natriuretic Agents
Physiological Effects of Drugs