Trial Summary
What is the purpose of this trial?This phase I trial tests the safety, side effects, and best dose of triapine in combination with temozolomide in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Triapine inhibits an enzyme responsible for producing molecules required for the production of deoxyribonucleic acid (DNA), which may inhibit tumor cell growth. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Giving triapine in combination with temozolomide may be safe, tolerable, and/or effective in treating patients with recurrent glioblastoma.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents, and there are specific time intervals required since your last cytotoxic therapy. It's best to discuss your current medications with the trial team to ensure eligibility.
What data supports the idea that Triapine + Temozolomide for Brain Tumors is an effective drug?
The available research shows that Temozolomide is widely used for treating brain tumors like glioblastoma multiforme and high-grade glioma. It is often used in combination with other treatments to improve effectiveness. For example, one study mentions that combining Temozolomide with other drugs may help overcome resistance and improve treatment outcomes. Although specific data on Triapine combined with Temozolomide is not provided, Temozolomide alone has shown promise in treating brain tumors, suggesting that combinations could be effective.
12345What safety data is available for the treatment of Triapine and Temozolomide for brain tumors?
The provided research does not contain safety data for the treatment of Triapine and Temozolomide (or its various names) for brain tumors. The studies focus on other compounds and their effects, such as anticonvulsant activity, metabolism, and pharmacokinetics, but do not address the safety or efficacy of Triapine and Temozolomide in the context of brain tumors.
678910Is the drug Temozolomide a promising treatment for brain tumors?
Yes, Temozolomide is a promising drug for brain tumors. It is effective against high-grade gliomas and glioblastoma multiforme, can be taken orally, and has a good safety profile. It also works well in combination with other treatments, making it a strong option for treating brain tumors.
12111213Eligibility Criteria
This trial is for patients with recurrent glioblastoma, a type of brain tumor. Participants should have experienced an improvement period before the cancer returned. The study will involve various procedures including MRI scans and possibly surgery.Inclusion Criteria
Patients must be able to undergo contrast-enhanced magnetic resonance imaging (MRI)
Patients must meet specific criteria for blood counts (leukocytes, absolute neutrophil count, hemoglobin, platelets), liver function (total bilirubin, AST/ALT), kidney function (creatinine), coagulation (INR, PT/PTT), and cardiac function
Patients of child-bearing potential (POCBP) must agree to use adequate contraception
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Exclusion Criteria
Patients who are receiving any other investigational agents except for COVID-19 vaccine and treatment
I do not have another cancer that could affect this study's treatment or safety.
I do not have severe allergies, uncontrolled illnesses, or issues that affect taking pills.
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Participant Groups
The safety and optimal dosage of triapine in combination with temozolomide are being tested. Triapine may stop tumor growth by blocking DNA production, while temozolomide damages tumor cell DNA to potentially slow or stop the tumor's progression.
2Treatment groups
Experimental Treatment
Group I: Groups 1 and 2 (temozolomide, triapine)Experimental Treatment5 Interventions
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
Group II: Group 3 (triapine, surgical resection, temozolomide)Experimental Treatment6 Interventions
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
Temozolomide is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Temodal for:
- Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
- Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy
🇺🇸 Approved in United States as Temodar for:
- Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
- Newly diagnosed or refractory anaplastic astrocytoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Northwestern UniversityChicago, IL
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Who Is Running the Clinical Trial?
Northwestern UniversityLead Sponsor
National Cancer Institute (NCI)Collaborator
BrainUp IncCollaborator
References
Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation. [2022]Currently temozolomide (TMZ) as a potent agent is widely used to treat the glioblastoma multiforme (GBM), whereas recurrence due to intrinsic or acquired therapeutic resistance often occurs. Combination chemotherapy with TMZ may be a promising therapeutic strategy to improve treatment efficacy.
Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. [2022]Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG.
Phase 2 trial of temozolomide using protracted low-dose and whole-brain radiotherapy for nonsmall cell lung cancer and breast cancer patients with brain metastases. [2022]Temozolomide (TMZ), an oral methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanomas, and brain metastasis and is presently administered as a 5-day oral schedule every 4 weeks.
Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]Label="BACKGROUND">Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20-100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients.
Future directions for temozolomide therapy. [2019]Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide. [2013]N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.
Structure-activity relationship and docking studies of thiazolidinedione-type compounds with monoamine oxidase B. [2016]The neuroprotective activity of pioglitazone and rosiglitazone in the MPTP parkinsonian mouse prompted us to evaluate a set of thiazolidinedione (TZD) type compounds for monoamine oxidase A and B inhibition activity. These compounds were able to inhibit MAO-B over several log units of magnitude (82 nM to 600 μM). Initial structure-activity relationship studies identified key areas to modify the aromatic substituted TZD compounds. Primarily, substitutions on the aromatic group and the TZD nitrogen were key areas where activity was enhanced within this group of compounds.
Disposition of two tetramethylcyclopropane analogues of valpromide in the brain, liver, plasma and urine of rats. [2019]2,2,3,3-Tetramethylcyclopropane carboxamide (TMCD) and N-methyl TMCD (M-TMCD) are analogues of valpromide (VPD) or amide derivatives of valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models both TMCD and M-TMCD are more potent as anticonvulsants than VPA. The present study investigates the pharmacokinetics (PK) of TMCD and M-TMCD in rats by monitoring the levels of these two amides in the brain, liver, plasma and urine of rats. The disposition of TMCD and M-TMCD was analyzed in a comparative manner with that of VPD and VPA, previously studied by us. The following similar PK parameters were obtained for TMCD and M-TMCD, respectively: clearance, 5 and 5.6 ml/min/kg; volume of distribution (Vss), 0.72 and 0.96 l/kg; half-life (t1/2), 1.1 and 1. 2 h; and mean residence time (MRT), 2.41 and 2.8 h. The ratio of AUCs of TMCD of liver to plasma and brain to plasma were 1.67 and 1. 13, respectively. The ratios of the AUCs of M-TMCD of liver to plasma and brain to plasma were 1.43 and 0.99, respectively. Thus, both compounds distribute evenly between plasma and brain, but their distribution into the liver is 50% larger than that in the plasma. Therefore, PK analysis of TMCD and M-TMCD brain levels gave major PK parameters similar to those obtained from the plasma data. The fraction metabolized of M-TMCD to TMCD was 32%. The brain was not found to be a metabolic site for the M-TMCD to TMCD biotransformation which occurred primarily in the liver as indicated by the high liver concentrations of TMCD as a metabolite of M-TMCD. Unlike VPD, TMCD and M-TMCD did not undergo amide-acid biotransformation to their corresponding inactive acid, 2,2,3, 3-tetramethylcyclopropane carboxylic acid (TMCA). Both M-TMCD and TMCD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.
Anticonvulsant activity and monoamine oxidase inhibitory properties of substituted 1,2,4-triazoles. [2006]Nine 5-(3,4,5-trimethoxyphenyl)-4-substituted aryl-3-hydrazinocarbonylmethylthio-4H-1,2,4-triazoles were investigated for their anticonvulsant and monoamine oxidase inhibitory properties. The protection afforded by these compounds at a dose of 100 mg/kg ranged from 20-90% against pentylenetetrazol-induced seizures and 20-40% against electric shock-induced convulsions. The degree of in vitro monoamine oxidase inhibition by substituted triazoles ranged from 41-80%, 18-36% and 20-40% using kynuramine, tyramine and 5-hydroxytryptamine as substrate, respectively. The approximate LD50 values of greater than 1000 mg/kg exhibited low toxicity of substituted triazoles.
Metabolism and excretion of TH-302 in dogs. [2012]The metabolism and excretion of a hypoxically activating prodrug for the treatment of cancer, TH-302, were studied in beagle dogs following intravenous administration of 20 mg/kg (14)C-TH-302. TH-302 was extensively metabolized with total recovery of 75.1%, with 47.5% and 25.3% excreted through the urine and through the bile into the feces, respectively. The three TH-302 metabolites in plasma were: DM7, a conjugate of TH-302 with glutathione replacing a bromine atom; DM5, a hydrolysis product of DM7 with loss of the glutamic acid moiety; and DM6, a hydrolysis product of DM5 with loss of the glycine moiety. DM6 and TH-302 were the major radioactive components in plasma and accounted for 69.8% and 27.3% of the total AUC, respectively. The major metabolite in urine was DM6, which accounted for 22.7% of the administered dose. Two other metabolites identified in urine were: DM3, a dicysteine conjugate of TH-302; and DM4, which was formed by hydrolysis and loss of the 1-methyl-2-nitro-imidazol-5-yl methoxy moiety, followed by oxidation on the cysteinyl ethylamine moiety. DM1 and DM2 in urine accounted for 6.50 and 7.76% of administered dose and were not identified. DM1 was the only fecal metabolite. Further investigations are required to completely characterize the metabolism of TH-302.
Temozolomide in combination with other cytotoxic agents. [2019]Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) has several characteristics that make it appealing for combination therapies: broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. Preclinical and phase I trials have shown the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. Toxicity is lower and the maximum tolerated dose is higher when carmustine is given before temozolomide. Studies also have examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 was more effective than either agent alone. A major issue facing investigators now is determining which of the several schedules of temozolomide and CPT-11 are optimal. Completed and ongoing studies of temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described.
Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. [2018]Temozolomide (TMZ) is an oral alkylating agent with demonstrated efficacy as therapy for glioblastoma multiforme (GBM) and anaplastic astrocytoma. TMZ has widely replaced the procarbazine, lomustine plus vincristine (PCV) combination for the treatment of malignant brain tumours as a result of its oral administration and favourable toxicity profile.
An efficient and practical radiosynthesis of [11C]temozolomide. [2021]Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [(11)C]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [(11)C]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [(11)C]TMZ with a radiochemical yield of 17 ± 5% and ≥97% radiochemical purity is reported.