Methimazole for the Treatment of Patients with Glioblastoma
This phase II trial evaluates the safety and effectiveness of giving methimazole before and after surgery for the treatment of patients with glioblastoma that is growing, spreading, or getting worse (progressive) or that has come back (recurrent). Deficiencies in hydrogen sulfide production have been associated with cancer while the presence of hydrogen sulfide has been shown to suppress the survival of glioblastoma cancer cells. Methimazole is a drug approved by the Food and Drug Administration for the treatment of overactive thyroid. It works to prevent the production of thyroid hormones. It may boost production of hydrogen sulfide, which could inhibit the survival of glioblastoma cancer cells.
Inclusion Criteria
- Subjects must have histologically or cytologically confirmed World Health Organization (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 >= 18 years
- Performance status: Karnofsky performance status >= 70%
- Hemoglobin >= 8 g/dl (within 21 days of study entry)
- Absolute neutrophil count >= 1,200/mcL (within 21 days of study entry)
- Platelet count >= 75,000/mcL (within 21 days of study entry)
- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (within 21 days of study entry)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 x institutional ULN (within 21 days of study entry)
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (within 21 days of study entry)
- Calculated creatinine clearance >= 50 mL/min (within 21 days of study entry)
- Prothrombin time/international normalized ratio (PT/INR) < 1.4 for patients not on warfarin (within 21 days of study entry)
- Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria (within 21 days of study entry): * No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) * In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
- Subjects must have normal thyroid function within 21 days of study entry as defined below: * =< 3 X institutional ULN
- Women of childbearing potential must have a negative pregnancy test within 21 days of study entry. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men of reproductive potential treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 30 days after the last dose of study drug
- Patients must be able to swallow whole tablets
- Patients must have the following minimum intervals from prior treatments: * Surgery – 4 weeks * Nitrosoureas – 6 weeks * Cytotoxic chemotherapy – standard intervals depending on the most recent regimen. i.e., for temozolomide 5 of 28, 23 days after most recent temozolomide; for temozolomide 21 of 28 days, 7 days after most recent dose; etoposide 14 of 21 days, 7 days after last dose. For drugs not listed, the research nurse, treating investigator, and principal investigator will determine the appropriate interval * Investigational therapy or non-cytotoxic therapy – 2 weeks * For bevacizumab - 4 weeks from anticipated date of protocol surgery
- Patients positive for human immunodeficiency virus (HIV) are allowed on study (note: HIV testing is not required), but HIV-positive patients must have: * An undetectable viral load within 6 months of registration. * A stable regimen of highly active anti-retroviral therapy (HAART) * No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Note: A known positive test for HBV surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g., patients immunized against hepatitis B)
- For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Note: Know positive test for HCV ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
- Patient must be deemed by investigator to be a candidate for post-operative chemotherapy
- Subjects must have the ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Prior treatment toxicities not resolved to =< grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 except alopecia and neuropathy
- Subjects receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to methimazole
- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Other prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are excluded. Otherwise, patients with prior or concurrent malignancy are eligible
- Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, malabsorption, or grade >= 2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v.5.0] diarrhea of any etiology at screening)
- Pregnant or breastfeeding
- Known history of hyperthyroidism or hypothyroidism
- Unable or unwilling to swallow tablets
- Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator’s judgment, make the patient inappropriate for this study
Additional locations may be listed on ClinicalTrials.gov for NCT05607407.
Locations matching your search criteria
United States
Ohio
Cleveland
PRIMARY OBJECTIVE:
I. To obtain a signal for efficacy as measured by progression-free survival rate at 6 months (PFS6 – defined as alive and free from progressive disease) after methimazole administration concurrent with standard of care chemotherapy.
SECONDARY OBJECTIVES:
I. To generate a 10% increase in hydrogen sulfide (H2S) production capacity and 1.5-fold increase in total sulfhydration signaling in peripheral blood from patients treated with methimazole concurrent with standard of treatment chemotherapy.
II. To observe safety and toxicity of standard dose methimazole administration concurrent with standard of care chemotherapy.
EXPLORATORY OBJECTIVES:
I. To discover specific proteins sulfhydrated that are known to impact glioblastoma (GBM) progression and/or treatment resistance.
II. To measure concentration of H2S in brain tissue after treatment with methimazole.
OUTLINE: This is a dose-escalation study.
Patients receive methimazole orally (PO) 5 days before surgical resection with last dose on the morning of surgery and then again starting 1-14 days after surgery. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients receive standard of care (SOC) chemotherapy starting 1-28 days after surgery. Patients also undergo collection of blood samples and magnetic resonance imaging (MRI) throughout the trial.
After completion of study treatment, patients will be followed up at 30 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationCase Comprehensive Cancer Center
Principal InvestigatorDavid Marc Peereboom
- Primary IDCASE3322
- Secondary IDsNCI-2023-01718
- ClinicalTrials.gov IDNCT05607407