Trial Title:
Methimazole in Patients With Progressive Glioblastoma
NCT ID:
NCT05607407
Condition:
Glioblastoma
Glioma
Conditions: Official terms:
Glioblastoma
Methimazole
Conditions: Keywords:
Transsulfuration
Methimazole
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Methimazole
Description:
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.
Arm group label:
Surgical Resection, Pharmacodynamic Assays, and Methimazole
Other name:
Northyx
Other name:
Tapazole
Intervention type:
Procedure
Intervention name:
Recurrent Glioblastoma Surgical Resection
Description:
The purpose of resection is to remove as much tumor as possible to alleviate mass effect
and to obtain brain tissue for experimental analysis.
Arm group label:
Surgical Resection, Pharmacodynamic Assays, and Methimazole
Intervention type:
Diagnostic Test
Intervention name:
Pharmacodynamic Assays
Description:
Pharmacodynamic assays are intended to investigate drug and downstream drug-induced
effects.
Arm group label:
Surgical Resection, Pharmacodynamic Assays, and Methimazole
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.
Detailed 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 synthesis and signaling represents a safe and promising method to mitigate disease
progression. Based on previously published data, which detailed the use of the thyroid
hormone inhibitor propylthiouracil (PTU) to enhance endogenous H2S production in mice,
and a previous clinical trial at CCF utilizing PTU to increase the survival of
glioblastoma patients, revisiting the use of thyroid hormone inhibitors to de-repress
endogenous H2S production concurrent with standards of care poses a novel therapeutic
avenue. In the nearly two decades since the aforementioned clinical trial, PTU has been
largely replaced in clinical endocrinology by the safer and more efficient thyroid
inhibitor methimazole. Given our recent success elucidating the importance of tumor
suppressive H2S in the realm of GBM, it is hypothesized that reduced thyroid hormone
production via oral methimazole intake will bolster the effectiveness of frontline
therapy and extend survival by boosting H2S production and function within the
tumor-bearing brain. The goal of this trial is to provide proof of the concept that
suppression of thyroid hormone signaling via methimazole and subsequent augmentation of
H2S synthesis and signaling is feasible in patients with glioblastoma. Achievement of
this goal will motivate and guide further therapeutic development of this combinatorial
therapeutic approach.
Criteria for eligibility:
Criteria:
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 ≥ 75,000/mcL, Total bilirubin < 1.5 x institutional upper
limit of normal (ULN), AST (SGOT) ≤ 3 X institutional ULN, ALT (SGPT) ≤ 3 X
institutional ULN, Calculated creatinine clearance > 50 mL/min, Prothrombin
time/international normalized ratio (PT/INR) <1.4 for patients not on warfarin,
Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both
of the following criteria: 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.
- 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
- 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 NCI 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
Address:
City:
Cleveland
Zip:
44195
Country:
United States
Status:
Recruiting
Contact:
Last name:
David Peereboom, MD
Phone:
866-223-8100
Email:
TaussigResearch@ccf.org
Start date:
January 30, 2023
Completion date:
January 2026
Lead sponsor:
Agency:
Case Comprehensive Cancer Center
Agency class:
Other
Source:
Case Comprehensive Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05607407
