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

Trial Summary

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.

What data supports the effectiveness of the drug Tirapazamine for liver cancer?

Research shows that Tirapazamine, when used with other treatments like cisplatin or radiation, has shown promising results in treating solid tumors by targeting low-oxygen areas in tumors. This suggests potential effectiveness when combined with embolization for liver cancer. ^{1 2 3 4 5}

Is the combination of Tirapazamine and Embolization safe for liver cancer treatment?

Tirapazamine combined with embolization has been studied for safety in liver cancer treatment. In clinical trials, it was generally well-tolerated, with some patients experiencing mild liver enzyme changes that returned to normal. Muscle cramping was noted in some studies, but overall, the treatment was considered safe at certain doses. ^{1 3 4 6 7}

What makes the drug Tirapazamine unique for liver cancer treatment?

Tirapazamine is unique because it is activated in low-oxygen environments, like those found in tumors, making it particularly effective when combined with embolization (blocking blood flow to the tumor) for treating liver cancer. This approach is different from standard treatments as it specifically targets the hypoxic (low oxygen) areas of tumors, potentially enhancing the effectiveness of the treatment. ^{1 2 4 5 8}

What is the purpose of this trial?

This phase 1 study is to determine the optimal dose and tolerability of a hypoxia-activating agent, tirapazamine, when it is combined with embolization in liver cancer. Liver cancer patients who are Child-Pugh score A, suitable for embolization with tumor no more than 4 nodules are eligible. Tirapazamine will be given by intra-arterial injection before embolization. Treatment effect is evaluated by MRI based on mRECIST criteria. Repeat treatment is necessary only if disease progression. Dose escalation cohort has been completed. Expansion cohort is open for metastatic liver dominant neuroendocrine tumor.

Research Team

Michael Soulen, MD

Principal Investigator

Univ. of Pennsylvania

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase I Dose-Escalation Study of Tirapazamine Chemoembolization for Unresectable Early- and Intermediate-Stage Hepatocellular Carcinoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

1,2,4-Benzotriazine 1,4-dioxides. An important class of hypoxic cytotoxins with antitumor activity. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation. [2019]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Phase I Trial on Arterial Embolization with Hypoxia Activated Tirapazamine for Unresectable Hepatocellular Carcinoma. [2022]

5. United States 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. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer. [2019]

7. United States 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Microdialysis sampling with on-line microbore HPLC for the determination of tirapazamine and its reduced metabolites in rats. [2019]