Triapine + Temozolomide for Brain Tumors

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must not be taking: Investigational agents

Disqualifiers: Concurrent malignancy, G6PD deficiency, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 11

Duration: 24 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safe and effective dose of a drug combination for treating recurring brain tumors, specifically glioblastoma that has returned after initial treatment. It combines two drugs, triapine (a potential cancer treatment) and temozolomide (a chemotherapy drug), to assess their ability to safely work together to halt tumor growth. Triapine may block tumor growth by interfering with tumor cell DNA production, while temozolomide may kill tumor cells by damaging their DNA. Individuals with recurrent glioblastoma who have had stable or decreasing doses of certain medications, such as corticosteroids, might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Will I have to stop taking my current medications?

The trial information 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 treatment with certain drugs. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using triapine with temozolomide might be safe and manageable for treating recurrent glioblastoma, a type of brain tumor. Triapine blocks an enzyme that aids tumor cell growth, while temozolomide damages the DNA of these cells to slow or stop their growth.

Although specific side effects from this combination are not yet detailed, temozolomide is a well-known drug already used to treat brain tumors, with a recognized safety record. The trial is in its early stages, focusing on finding the best dose and identifying any safety issues. While there is hope for safety, the combination is still being carefully tested to ensure it is well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Triapine and Temozolomide for brain tumors because this combination targets cancer cells in a unique way. Unlike standard treatments, such as radiation and traditional chemotherapy, which generally attack both healthy and cancerous cells, Triapine specifically inhibits an enzyme critical for cancer cell DNA replication. This targeted approach could potentially reduce side effects and improve effectiveness. Additionally, in one of the treatment groups, Triapine is given before surgery to shrink tumors, potentially making surgical removal more successful. This innovative combination and timing of treatments offer a promising new strategy for tackling brain tumors.

What evidence suggests that this trial's treatments could be effective for recurrent glioblastoma?

Research has shown that using triapine with temozolomide might help treat recurrent glioblastoma, a type of brain tumor. In this trial, participants in Groups 1 and 2 will receive both temozolomide and triapine. Triapine blocks an enzyme that tumors need to grow, potentially stopping tumor growth. Studies have found that triapine can enhance the effectiveness of temozolomide, a drug that damages tumor cell DNA. This suggests that the combination could be more effective at treating brain tumors than temozolomide alone. Early results indicate that this combination might be safe and manageable for patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Karan Dixit

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive temozolomide and triapine orally on days 1-5 of each 28-day cycle for up to 6 cycles

24 weeks

6 visits (in-person)

Surgical Resection (Group 3 only)

Patients in Group 3 receive triapine for 5 days prior to surgical resection

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

24 months

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Temozolomide
• Triapine

Trial Overview

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.

How Is the Trial Designed?

Group I: Groups 1 and 2 (temozolomide, triapine) Experimental Treatment 5 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 Treatment 6 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

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

BrainUp Inc

Collaborator

Trials

1

Recruited

30+

Published Research Related to This Trial

Temozolomide (TMZ) is shown to be more cost-effective than the traditional PCV treatment for glioblastoma multiforme (GBM), with costs of €2367 per extra life-month and €32,471 per quality-adjusted life-year (QALY).

The analysis indicates that TMZ has a high probability (over 60%) of being the most cost-effective treatment option at various willingness-to-pay thresholds, especially when considering quality of life improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. Martikainen, JA., Kivioja, A., Hallinen, T., et al.[2018]

Aspirin combined with temozolomide (TMZ) in coloaded microspheres showed enhanced antitumor effects against glioblastoma cells, leading to increased apoptosis and reduced cell proliferation compared to TMZ alone.

The combination therapy works by inhibiting β-catenin signaling, which is linked to tumor growth, and allows for a sustained release of TMZ, potentially reducing the required dosage while improving treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin-/TMZ-coloaded microspheres exert synergistic antiglioma efficacy via inhibition of β-catenin transactivation. Shi, ZD., Qian, XM., Liu, CY., et al.[2022]

In a study involving beagle dogs, the cancer treatment prodrug TH-302 was found to be extensively metabolized, with 75.1% of the administered dose recovered, primarily through urine (47.5%) and feces (25.3%).

The major metabolites identified in plasma were DM6 and TH-302 itself, which together accounted for nearly 97% of the total exposure, indicating that understanding these metabolites is crucial for evaluating the drug's efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism and excretion of TH-302 in dogs. Jung, D., Jiao, H., Duan, JX., et al.[2012]

OM-TMCD, a new anticonvulsant derived from valproic acid, showed better potency than valproic acid in various seizure tests in rats, indicating its potential as a more effective treatment for seizures.

While OM-TMCD has similar fetal toxicity risks as valproic acid, its enhanced anticonvulsant effects suggest a more favorable safety profile, making it a promising candidate for further research in epilepsy treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide. Sobol, E., Yagen, B., Lamb, JG., et al.[2013]

Pioglitazone and rosiglitazone, known for their neuroprotective effects in a mouse model of Parkinson's disease, led to the evaluation of other thiazolidinedione (TZD) compounds for their ability to inhibit monoamine oxidase A and B (MAO-A and MAO-B).

The study found that these TZD compounds could inhibit MAO-B across a wide range of concentrations, and modifications to the aromatic group and TZD nitrogen were crucial for enhancing their inhibitory activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-activity relationship and docking studies of thiazolidinedione-type compounds with monoamine oxidase B. Carroll, RT., Dluzen, DE., Stinnett, H., et al.[2016]

In a randomized trial involving 447 patients with recurrent high-grade glioma, temozolomide (TMZ) did not show a clear survival advantage over procarbazine, lomustine, and vincristine (PCV), with a hazard ratio of 0.91, indicating similar effectiveness.

However, within the TMZ treatment groups, the 5-day regimen demonstrated better overall progression-free survival and quality of life compared to the 21-day regimen, suggesting that shorter treatment schedules may be more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. Brada, M., Stenning, S., Gabe, R., et al.[2022]

In a phase 2 clinical trial involving 27 patients with brain metastases from breast cancer and non-small cell lung cancer, a new regimen combining whole-brain radiotherapy (WBRT) with a prolonged low-dose temozolomide (TMZ) treatment showed promising antitumor activity, achieving a 7.4% complete response and a 40.7% partial response.

The treatment was well tolerated, with only 2 patients experiencing grade 3 toxicity, and resulted in a median overall survival of 8.8 months and a median progression-free survival of 6 months, indicating its potential as a viable option for treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Addeo, R., De Rosa, C., Faiola, V., et al.[2022]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Nine new triazole compounds showed significant anticonvulsant effects, providing 20-90% protection against seizures induced by pentylenetetrazol and 20-40% protection against electric shock-induced convulsions at a dose of 100 mg/kg.

These compounds also demonstrated strong monoamine oxidase inhibition, with effects ranging from 41-80%, indicating potential mechanisms for their anticonvulsant activity, while exhibiting low toxicity with LD50 values greater than 1000 mg/kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticonvulsant activity and monoamine oxidase inhibitory properties of substituted 1,2,4-triazoles. Jaiswal, RK., Parmar, SS., Kumar, S., et al.[2006]

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

TMCD and M-TMCD are more potent anticonvulsants than valproic acid (VPA) in rodent models, suggesting they may be more effective treatments for epilepsy.

Both compounds show favorable pharmacokinetics, distributing well into the brain and liver, with M-TMCD metabolizing to TMCD primarily in the liver, which may enhance their anticonvulsant effects compared to VPA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition of two tetramethylcyclopropane analogues of valpromide in the brain, liver, plasma and urine of rats. Blotnik, S., Bergman, F., Bialer, M.[2019]

A new one-pot method for synthesizing the positron-emitting version of temozolomide, [(11)C]TMZ, has been developed, achieving a consistent radiochemical yield of 17 ± 5% and high purity (≥97%).

This improved synthesis method addresses previous challenges in producing [(11)C]TMZ, potentially facilitating its routine use in studying the mechanism and distribution of temozolomide in treating malignant brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An efficient and practical radiosynthesis of [11C]temozolomide. Moseley, CK., Carlin, SM., Neelamegam, R., et al.[2021]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

In a study of 31 pretreated patients with non-small cell lung cancer (NSCLC), temozolomide showed minimal efficacy as a salvage therapy, with only 6.5% achieving a partial response and a median survival time of 3.3 months.

Despite its limited effectiveness, the treatment was generally well-tolerated, although there was one toxic death due to severe neutropenia, highlighting the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study. Kouroussis, C., Vamvakas, L., Vardakis, N., et al.[2018]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

Temozolomide (TMZ) is well tolerated in patients with glioma and melanoma, with dose-limiting toxicity primarily being thrombocytopenia, observed at maximum tolerated doses of 150 mg/m2/day for patients with prior nitrosourea exposure and 250 mg/m2/day for those without.

The study showed promising antitumor activity, with two complete responses in patients without prior nitrosourea treatment, suggesting that TMZ could be an effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Dhodapkar, M., Rubin, J., Reid, JM., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Citations

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clinicaltrials.gov

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Giving triapine in combination with temozolomide may be safe, tolerable, and/or effective in treating patients with recurrent glioblastoma. Detailed Description.

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Ribonucleotide reductase regulatory subunit M2 drives ...

In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously ...

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sciencedirect.com

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Triapine inhibition of RRM2 sensitizes GBM to ionizing radiation treatment. Simultaneous RRM2 and CHK1 inhibition induce synthetic lethality in GBM.

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Our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo.

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A potent inhibitor of ribonucleotide reductase activity with ...

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We have synthesized 3-AP and demonstrated (a) potent inhibition of L1210 leukemia cells in vitro, (b) curative capacity for mice bearing the L1210 leukemia.

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clin.larvol.com

clin.larvol.com/trial-detail/NCT06410248

Triapine in Combination With Temozolomide for the ...

The primary objective of this phase 1 study will be to determine the recommended phase 2 dose (RP2D) for Triapine in combination with temozolomide (TMZ).

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Link to Protocol - IROC Houston - MD Anderson Cancer Center

... data on safety, tolerability, and preliminary activity on doses below the MTD. ... Trapine® oral capsules (3-aminopyridine-2-carboxaldehyde thiosemicarbazone or 3 ...