Targeting Transsulfuration Via Suppression of Thyroid Hormone Signaling in Progressive Glioblastoma: Phase 2 and Pharmacodynamic Trial of Methimazole in Patients With Progressive Glioblastoma
Case Comprehensive Cancer Center
Summary
The purpose of this study is to test the effectiveness, safety, and tolerability of a drug called Methimazole. The investigational drug, Methimazole is not FDA approved for brain tumors, but it is used to treat thyroid illnesses. Different doses of Methimazole will be given to several study participants with glioblastoma. The first several study participants will receive the lowest dose. If the drug does not cause serious side effects, it will be given to other study participants at a higher dose. The doses will continue to increase for every group of study participants until the side effects occur that require the dose to be lowered. The procedures in this study are research blood draws, physical exams, collection of medical history, MRI scans, and study drug administration.
Description
Hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits the growth of cultured glioblastoma cells and impairs progression of glioblastoma tumors developing in vivo in laboratory mice. Additionally, endogenous H2S production and signaling via protein sulfhydration are decreased in human glioblastoma brain tissues compared to non-cancerous brain tissue. Thus, boosting H2S levels is a promising and novel therapeutic strategy for treating glioblastoma. The use of exogenous H2S is difficult to translate to the clinic due to toxicity and volatility. Therefore, bolstering endogenous H2S…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: * Subjects must have histologically or cytologically confirmed WHO grade 4 glioma (including tumors with molecularly defined grade 4 astrocytoma) for which a clinically indicated tumor resection is planned. * Subjects must not have received methimazole for this disease. * Age is greater than or equal to 18 years of age * Performance status: Karnofsky Performance status ≥ 70% * Subjects must have adequate organ function and laboratory parameters within 21 days of study entry as defined below: Hemoglobin ≥ 8 g/dl, Absolute neutrophil count ≥ 1,200/mcL, Platelet count ≥ 75,00…
Interventions
- DrugMethimazole
Starting dose: Methimazole 15 mg/d. Six participants will receive this dose. If they achieve a 10% increase in peripheral blood H2S concentrations, an additional 13 participants will receive this dose to accrue a total of 19 participants for which a preliminary estimate of PFS6 can be calculated. If the first 6 participants do not achieve a 10% increase in peripheral blood H2S concentrations, the dose will be increased to the second and final dose level of 25 mg/d at which 19 participants will be treated.
- ProcedureRecurrent Glioblastoma Surgical Resection
The purpose of resection is to remove as much tumor as possible to alleviate mass effect and to obtain brain tissue for experimental analysis.
- Diagnostic TestPharmacodynamic Assays
Pharmacodynamic assays are intended to investigate drug and downstream drug-induced effects.
Location
- Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer CenterCleveland, Ohio