TATE + PD-1 Inhibitor for Liver Cancer

(TATE-PD1 Trial)

Recruiting at 2 trial locations

Overseen By Chiwei Lu, PhD.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Teclison Ltd.

Must be taking: Immune checkpoint inhibitors

Disqualifiers: Major autoimmune disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: up to 24 months

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination treatment for advanced liver cancer (hepatocellular carcinoma) or metastatic gastric cancer. The treatment uses Trans-arterial Tirapazamine Embolization (TATE) followed by a PD-1 inhibitor, such as Nivolumab or Opdivo, which are injectable products that help the immune system fight cancer. The researchers aim to determine if this combination can help when previous immune therapies or chemotherapy have failed. Suitable candidates have liver tumors, with at least one tumor larger than 2 cm, and have not responded to other treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that all prior chemotherapy be stopped at least 4 weeks before starting the study treatment. Immunotherapy does not have this limitation, so you may not need to stop it.

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

Previous studies have used nivolumab, a medication that blocks PD-1, to treat liver cancer. Some patients experienced serious side effects. For instance, one study found that 0.9% of patients had severe reactions such as lung inflammation and muscle weakness. Although rare, these side effects are important to note.

Research has shown that trans-arterial tirapazamine embolization (TATE) is generally safe and well-tolerated. Patients with liver cancer who received TATE did not report major safety issues. Researchers continue to study this treatment to ensure its safety and effectiveness.

Both treatments have been tested in humans, but ongoing studies like this one are crucial to further understanding their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for liver cancer, which typically involves systemic chemotherapy or targeted therapies, the combination treatment of a PD-1 inhibitor like Nivolumab with trans-arterial tirapazamine embolization (TATE) is unique because it merges immunotherapy with localized cancer treatment. The PD-1 inhibitors, such as Nivolumab, Opdivo, or Keytruda, work by enhancing the immune system's response against cancer cells, potentially offering a more targeted attack than traditional chemotherapy. TATE adds a novel approach by directly targeting the liver tumor with a potent anticancer agent, tirapazamine, before embolization, which may help in shrinking the tumor locally. Researchers are excited about this combination because it not only leverages the body's own immune defenses but also provides a focused, aggressive treatment that could improve outcomes for patients with advanced liver cancer.

What evidence suggests that this trial's treatments could be effective for liver cancer?

This trial will evaluate the combination of treatments for liver cancer, including the PD-1 inhibitor Nivolumab and Trans-arterial Tirapazamine Embolization (TATE). Studies have shown that Nivolumab effectively treats advanced liver cancer, with more patients experiencing tumor shrinkage compared to some other treatments. Patients with liver cancer that cannot be surgically removed have seen positive results with Nivolumab. TATE targets and destroys liver tumor cells by cutting off their blood supply. This combination of treatments aims to improve outcomes for patients whose cancer has worsened after other immune therapies. Early research suggests this approach could significantly help people with liver tumors, but more studies are needed to confirm these benefits. ^{2 3 6 7 8}

Who Is on the Research Team?

Nadine Abi-Jaoudeh, MD

Principal Investigator

UC Irvine Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with advanced liver cancer (HCC) or metastatic stomach cancer, who have not responded to prior immune therapy. HCC patients must have a Child-Pugh score of 5-7 and all participants should be relatively fit (ECOG score ≤2), with normal organ function and at least one treatable liver tumor.

Inclusion Criteria

I have not had serious stomach or intestinal bleeding in the last 2 months.

Hgb>=8, platelet >= 50,000, Cr =< 2, AST and ALT < 10 X ULN, t-Bilirubin < 3

My liver or stomach cancer has worsened despite immune therapy.

Exclusion Criteria

Patients with a history of major autoimmune disorders

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 4 cycles of TATE treatment starting at day 8, followed by PD-1 inhibitor (Nivolumab) until progression

up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 24 months

Open-label extension (optional)

Participants may continue receiving PD-1 inhibitor treatment if beneficial

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab Injectable Product
• Opdivo Injectable Product or Keytruda Injectable Product
• Trans-arterial tirapazamine embolization

Trial Overview The study tests TATE, a targeted liver cancer treatment, followed by Nivolumab, an immunotherapy drug. It's designed to see how well these treatments work together in patients with specific types of advanced or metastatic cancers that affect the liver.

How Is the Trial Designed?

Group I: Metastatic Gastro-esophageal cancer Experimental Treatment 2 Interventions

PD-1 inhibitor (Nivolumab 360 mg Q3W IV) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.

Group II: Advanced Hepatocellular carcinoma Experimental Treatment 2 Interventions

PD-1 inhibitor (Nivolumab 360 mg Q3W IV ) starts at day 1, and continues until progression. TATE treatment starts at day 8 for debulking up to 4 cycles. If escape lesion appears, two more TATE treatments can be given. Tirapazamine dose at 35 mg flat dose given before embolization.

Nivolumab Injectable Product is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Hepatocellular carcinoma
• Colorectal cancer
• Esophageal squamous cell carcinoma

Approved in United States as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Hepatocellular carcinoma
• Colorectal cancer
• Esophageal squamous cell carcinoma

Approved in Japan as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Hepatocellular carcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Hepatocellular carcinoma
• Colorectal cancer

Who Is Running the Clinical Trial?

Teclison Ltd.

Lead Sponsor

Trials

4

Recruited

200+

Published Research Related to This Trial

The PETAL trial is a phase Ib study designed to evaluate the safety and preliminary efficacy of pembrolizumab, an anti-PD-1 antibody, in patients with intermediate-stage hepatocellular carcinoma (HCC) after undergoing transarterial chemoembolization (TACE).

The study will initially assess safety in a run-in phase with six patients, followed by enrollment of up to 26 additional participants, with pembrolizumab treatment starting 30-45 days post-TACE and continuing for up to one year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma. Fessas, P., Scheiner, B., D'Alessio, A., et al.[2023]

In the safety run-in of the IMMUNOBIL PRODIGE 57 trial involving 20 patients, the combination of durvalumab and tremelimumab with paclitaxel resulted in a high rate of dose-limiting toxicities (50%), including serious anaphylactic reactions and other severe adverse events.

Due to the safety concerns raised by the combination therapy, the trial will proceed with only the durvalumab and tremelimumab combination, indicating that the addition of paclitaxel may not be safe for patients with advanced biliary tract carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Boilève, A., Hilmi, M., Gougis, P., et al.[2021]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

Nivolumab, an immune checkpoint inhibitor, appears to be safe for patients with end-stage renal disease (ESRD) and metastatic renal cell carcinoma (mRCC), as none of the three reported cases experienced severe toxicities during treatment.

Among the patients treated with nivolumab, two achieved a partial response, indicating that this therapy can provide clinical benefits for ESRD patients, suggesting that dose adjustments may not be necessary for those on dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes and Safety of Biweekly and Monthly Nivolumab in Patients with Metastatic Renal Cell Carcinoma and Dialysis: Three Case Reports and Literature Review. Osmán-García, I., Congregado-Ruiz, CB., Lendínez-Cano, G., et al.[2021]

Tremelimumab is a fully human IgG2 antibody targeting CTLA4, currently in phase III trials for malignant melanoma and phase II trials for several other cancers, indicating its broad potential in cancer treatment.

The drug is being investigated for multiple cancer types, including colorectal, gastrointestinal, gynecological, non-small cell lung, prostate, breast, and pancreatic cancers, showcasing its versatility in oncology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab. [2023]

The combination of bempegaldesleukin (BEMPEG) and nivolumab (NIVO) has shown promising results as a well-tolerated first-line treatment for metastatic melanoma, indicating its potential effectiveness in this patient population.

The ongoing PIVOT-12 study aims to determine if BEMPEG plus NIVO can improve recurrence-free survival compared to NIVO alone in patients with completely resected stage III/IV melanoma, which could provide important insights into its efficacy as an adjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PIVOT-12: a phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence. Eggermont, AM., Ascierto, PA., Khushalani, NI., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Nivolumab has been demonstrated to be an effective treatment for hepatocellular carcinoma (HCC), indicating its potential as a therapeutic option for this type of liver cancer.

The treatment is also reported to be safe, suggesting that it can be administered with a manageable side effect profile for patients with HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Programmed death-1 therapy in advanced hepatocellular carcinoma: A real-world experience. Al Jarroudi, O., Chaabouni, H., Ulusakarya, A., et al.[2021]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/hcc

Efficacy Data for Hepatocellular Carcinoma (HCC) Liver-related serious adverse reactions occurred in 17% of patients receiving OPDIVO with YERVOY, including Grade 3-4 events in 16% of patients. The most ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7338665/

Real-World Outcomes of Nivolumab in Patients With ... In conclusion, our study demonstrates that nivolumab monotherapy is clinically efficacious in treating unresectable HCC in an endemic area of HBV infection.

3. opdivo.com opdivo.com/advanced-hcc/clinical-trial-results/unresectable-immunotherapy-combination

Clinical trial results for previously untreated advanced liver ... More people given OPDIVO + YERVOY had their tumors shrink or completely disappear compared to targeted therapies lenvatinib or sorafenib ...

4. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma

FDA approves nivolumab with ipilimumab for unresectable ... Median OS was 23.7 months (95% CI: 18.8, 29.4) in the nivolumab + ipilimumab arm and 20.6 months (95% CI: 17.5, 22.5) in the lenvatinib or ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9644453/

Low-dose nivolumab in advanced hepatocellular carcinoma Low-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC.

6. opdivohcp.com opdivohcp.com/safety/hcc/opdivo-yervoy

Safety Profile in Hepatocellular Carcinoma (HCC) - Opdivo Fatal adverse reactions occurring in 3 (0.9%) patients who received OPDIVO as a single agent; these included pneumonitis (n=2) and myasthenia gravis. In ...

7. karger.com karger.com/pjg/article/doi/10.1159/000543288/918492/Five-year-sustained-response-to-nivolumab-in

Five-Year Sustained Response to Nivolumab in ... Second-line nivolumab, although yielding a rapid clinical and biochemical response, was permanently ceased after 12 weeks due to a grade 3 ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)01331-4/fulltext

P-87 Real-world data of nivolumab in advanced ... Fifteen deaths (58%) were observed, 9 in second- and 4 in third- line. The median overall survival (OS) was 101 [36-178], 182 [121–188], and 195 weeks [87-209] ...