Study of Acetazolamide With Temozolomide in Adults With Newly Diagnosed or Recurrent Malignant Glioma

Sponsor

University of Chicago (Other)

Overall Status

Recruiting

CT.gov ID

NCT03011671

Collaborator

(none)

Enrollment

Location

Arm

47.9

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

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 temozolomide (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 Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

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 IDH Wildtype Glioblastoma

Actual Study Start Date :

Oct 3, 2018

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

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 Names: Temodar

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 Names:

Temodar

Outcome Measures

Primary Outcome Measures

Number of participants with adverse events [28 Days]
To determine the safety, tolerability and adverse event profile of adding acetazolamide to temozolomide in patients with newly diagnosed malignant astrocytoma.

Secondary Outcome Measures

Measure objective response rate (ORR); change in tumor size [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) [6 months]
Time until overall survival (OS) [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. [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 determine feasibility of cooperative interaction between multiple sites [End of study enrollment period (approximately 6 years)]
Feasibility to be determined based on ability to complete accrual to the study

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically proven, newly diagnosed IDH wildtype glioblastoma (GBM) 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.