Tirapazamine + Embolization for Liver Cancer

Recruiting at 3 trial locations

Overseen By Ray Lee

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Teclison Ltd.

Disqualifiers: Major cardiac, pulmonary, renal dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Until disease progression

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for liver cancer using tirapazamine, a drug that activates in low-oxygen areas like tumors, along with embolization to block blood flow to the cancer. The goal is to determine the best dose and assess how well participants tolerate this combination. It targets individuals with neuroendocrine tumors (NETs) that have primarily spread to the liver, regardless of the cancer's origin. Participants may have tried other treatments but should have tumors occupying less than half of their liver's volume. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it allows patients who have had prior FDA-approved treatments, so you might be able to continue some medications. It's best to discuss this with the trial team.

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

Research shows that tirapazamine targets areas of tumors with low oxygen, which are common in solid tumors like liver cancer. Studies indicate that tirapazamine specifically attacks these tumor cells, causing less harm to healthy cells.

In lab tests, tirapazamine proved more effective in low-oxygen conditions typical of cancerous tissue. This allows the drug to focus more on cancer cells and less on normal ones. However, it also showed increased harm to liver cells in low-oxygen environments, highlighting the need for careful dosing to avoid damage to healthy liver cells.

Other studies suggest that tirapazamine can damage the DNA of cancer cells, making it a strong partner in cancer treatment. This necessitates close monitoring during treatment. Overall, these findings suggest that while tirapazamine has potential, it must be used carefully to balance its cancer-fighting abilities with possible side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for liver cancer?

Unlike the standard treatments for liver cancer, which often include chemotherapy, surgery, or radiofrequency ablation, Tirapazamine offers a unique approach by specifically targeting low-oxygen areas within tumors. Most treatments struggle to reach and affect these hypoxic zones effectively, but Tirapazamine becomes activated in these low-oxygen environments, potentially increasing its effectiveness against cancer cells. Researchers are excited about this treatment because it could enhance the impact of embolization, a procedure that blocks blood flow to the tumor, by further weakening the cancer cells that survive in these challenging conditions. This dual-action approach may offer a more powerful option against metastatic liver lesions from neuroendocrine tumors (NET).

What evidence suggests that tirapazamine combined with embolization might be an effective treatment for liver cancer?

Research shows that tirapazamine becomes active in low-oxygen areas, such as those often found in tumors. Studies have found it particularly effective at targeting and killing these low-oxygen cancer cells. In this trial, participants will receive tirapazamine before undergoing embolization, a procedure that blocks blood flow to the tumor, to evaluate the response in metastatic liver lesions. Previous lab studies demonstrated that combining tirapazamine with embolization improved the ability to kill liver tumors. Additionally, tirapazamine made liver cancer cells more responsive to treatment. These findings suggest that tirapazamine could effectively treat liver cancer when used in this manner. ^{1 2 4 6 7}

Who Is on the Research Team?

Michael Soulen, MD

Principal Investigator

Univ. of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for liver cancer patients with a good performance status (ECOG score 0-1) and adequate liver function (Child-Pugh A or B7). Candidates should have no more than 4 tumor nodules, no portal vein invasion, and be between ages 20-80. Prior treatments are allowed if there's progression, but not within the last 4 weeks. Excluded are those with certain neuroendocrine tumors or metastatic solid tumors.

Inclusion Criteria

My cancer is mainly in my liver and has gotten worse there, no matter where it started.

I am eligible for TAE or TACE and do not have a blocked portal vein.

My liver tumors take up less than half of my liver.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of tirapazamine until the maximally tolerated dose is determined

Varies per cohort

Treatment

Participants receive intra-arterial tirapazamine followed by embolization to evaluate response in liver lesions

Until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Tirapazamine
• Transarterial Embolization (TAE)

Trial Overview The study tests the optimal dose of Tirapazamine combined with Transarterial Embolization (TAE) in treating liver cancer. Patients receive Tirapazamine intra-arterially before embolization to target hypoxic tumor areas. The treatment's effect is monitored by MRI using mRECIST criteria, with repeat treatments based on disease progression.

How Is the Trial Designed?

Group I: Tirapazamine Experimental Treatment 2 Interventions

Intra-arterial administration with tirapazamine before embolization to evaluate the response in metastatic liver lesions of NET

Who Is Running the Clinical Trial?

Teclison Ltd.

Lead Sponsor

Trials

4

Recruited

200+

Published Research Related to This Trial

Tirapazamine is a novel bioreductive cytotoxic agent that has shown promise in treating solid tumors, particularly in combination with cisplatin, as demonstrated in completed Phase III trials.

Research into tirapazamine derivatives has led to the identification of more effective analogues, such as SR 4895 and SR 4941, which exhibit improved in vivo activity against solid tumors, suggesting a potential for enhanced anticancer efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

1,2,4-Benzotriazine 1,4-dioxides. An important class of hypoxic cytotoxins with antitumor activity. Kelson, AB., McNamara, JP., Pandey, A., et al.[2018]

Tirapazamine, a hypoxic cytotoxic agent, was tested in three Phase I clinical trials to determine its maximum tolerated dose and effects on tumors, with doses ranging from 9 mg/m2 to 293 mg/m2, showing promise as a radiation enhancer.

The most common side effect reported was muscle cramping, which occurred across all dosing schedules but was not dose-limiting, indicating that tirapazamine can be administered safely while further studies continue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation. Doherty, N., Hancock, SL., Kaye, S., et al.[2019]

In a phase I study involving 12 patients with recurrent cervical carcinoma, the combination of tirapazamine and cisplatin was found to be safe, with a maximum tolerated dose of 330 mg/m2 for tirapazamine, while nausea and vomiting were the main side effects.

The treatment resulted in a 17% major response rate and a 25% minor response rate, indicating potential efficacy, particularly at the highest dose level tested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer. Aghajanian, C., Brown, C., O'flaherty, C., et al.[2019]

Tirapazamine (TPZ) administered via intra-arterial injection is tolerated in rats at doses up to 7 mg/kg, indicating its potential safety for clinical use in liver treatments.

While there were slight increases in serum alanine aminotransferase (ALT) levels, they remained below 100 U/L for most rats, and all values returned to baseline by day 14, suggesting minimal liver toxicity from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation. Liu, CH., Kuo, SM., Gao, HW., et al.[2022]

The combination of Tirapazamine (TPZ) and transarterial embolization (TAE) was found to be safe and well-tolerated in a Phase 1 trial involving 27 patients with unresectable hepatocellular carcinoma (HCC), with no serious drug-related adverse events reported.

The treatment showed promising efficacy, with 60% of patients achieving a complete response and 84% showing either complete or partial response, indicating that this combination therapy warrants further investigation in a Phase II trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma. Abi-Jaoudeh, N., Dayyani, F., Chen, PJ., et al.[2022]

A new online microdialysis HPLC method allows for the precise measurement of tirapazamine and its metabolites in rat blood and muscle tissue, achieving detection limits as low as 0.003 microM.

This method provides high temporal resolution for pharmacokinetic studies, enabling researchers to better understand how tirapazamine and its metabolites behave in the body after administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdialysis sampling with on-line microbore HPLC for the determination of tirapazamine and its reduced metabolites in rats. McLaughlin, KJ., Faibushevich, AA., Lunte, CE.[2019]

In a phase I study involving 17 patients with unresectable hepatocellular carcinoma (HCC), intra-arterial tirapazamine combined with transarterial chemoembolization (TACE) was well tolerated, with no dose-limiting toxicities or serious adverse events reported.

The treatment showed promising efficacy, with a complete response rate of 47% and a median overall survival of 29.3 months, supporting further investigation in a phase II study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Dose-Escalation Study of Tirapazamine Chemoembolization for Unresectable Early- and Intermediate-Stage Hepatocellular Carcinoma. Liu, CH., Peng, CM., Hwang, JI., et al.[2023]

In a phase I study involving 13 patients with lung cancer and other types, tirapazamine was safely combined with cisplatin, showing that full doses of both drugs could be tolerated together without affecting the clearance of cisplatin.

Partial responses were observed in two patients, indicating potential efficacy of the tirapazamine and cisplatin combination, which supports further investigation in phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. Johnson, CA., Kilpatrick, D., von Roemeling, R., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/2912562/

In vitro hepatotoxicity of SR 4233 (3-amino-1,2,4 ... - PubMed The 50% lethal dose of SR 4233 was found to be 50 times lower in hepatocyte monolayers at 1% O2 versus 20% O2. Even at 4% O2, a concentration that prevails in ...

2. pubs.acs.org pubs.acs.org/doi/10.1021/acs.chemrestox.6b00417

Cytotoxicity of Tirapazamine (3-Amino-1,2,4-benzotriazine-1,4 ... Tirapazamine (TPZ) is an anticancer drug with highly selective cytotoxicity toward hypoxic cells. TPZ is converted to a radical intermediate under hypoxic ...

3. aacrjournals.org aacrjournals.org/mct/article/13/3/630/91759/Tirapazamine-Sensitizes-Hepatocellular-Carcinoma

Tirapazamine Sensitizes Hepatocellular Carcinoma Cells to ... Tirapazamine (3-amino-1,2,4-benzotriazine 1,4 dioxide, SR4233) is a bioreductive drug belonging to the aromatic N-oxide family that has a selective toxicity for ...

4. sciencedirect.com sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tirapazamine

Tirapazamine - an overview Tirapazamine (3-amino-1,2,4-benzotriazine-1,4 dioxide) is an experimental anticancer drug that is activated to a toxic radical only in hypoxic conditions ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5081602/

Hypoxia-activated cytotoxic agent tirapazamine enhances ... This preclinical study showed that the combination of tirapazamine and arterial embolization is a regimen that improved the liver tumor-killing activity.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1968495/

a new anticancer drug exploiting hypoxia in solid tumours SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs.

7. researchgate.net researchgate.net/publication/311613753_Cytotoxicity_of_tirapazamine_3-amino-1_2_4-benzotriazine-1_4-dioxide-induced_DNA_damage_in_chicken_DT40_cells

induced DNA damage in chicken DT40 cells PDF | Tirapazamine (TPZ) is an anti-cancer drug with highly selective cytotoxicity to hypoxic cells. TPZ is converted to a radical ...