TATE + PD-1 Inhibitor for Liver Cancer

(TATE-PD1 Trial)

Recruiting at2 trial locations

Overseen by Nadine Abi-Jaoudeh, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Teclison Ltd.

Must be taking: Immune checkpoint inhibitors

Disqualifiers: Major autoimmune disorders, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a multi-center, open-label phase IIA study that investigates the preliminary efficacy of Trans-arterial Tirapazamine Embolization (TATE) treatment of liver cancer followed by a PD-1 checkpoint inhibitor (nivolumab). Patients with two types of cancers will be enrolled, advanced hepatocellular carcinoma (HCC),and metastatic gastric cancer. All enrolled patients need to have liver lesions and have progressed on a prior immune checkpoint inhibitor.

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.

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

Nivolumab has shown effectiveness in treating advanced melanoma, with improved survival rates and a favorable benefit-risk profile. While this data is specific to melanoma, it suggests potential for effectiveness in other cancers, including liver cancer. ^{1 2 3 4 5}

Is the combination of TATE and PD-1 inhibitors safe for humans?

Nivolumab and pembrolizumab, both PD-1 inhibitors, have been used safely in humans for conditions like melanoma and renal cell carcinoma, with common side effects including fatigue, nausea, and rash. In some cases, immune-related side effects like inflammation of the lungs or liver have been reported, but these treatments are generally considered safe with manageable side effects. ^{3 4 6 7 8}

What makes the TATE + PD-1 Inhibitor treatment for liver cancer unique?

This treatment combines trans-arterial tirapazamine embolization (TATE) with PD-1 inhibitors like Nivolumab or Keytruda, which is unique because it uses a targeted approach to deliver chemotherapy directly to the liver tumor while also enhancing the immune system's ability to fight cancer. This dual approach may offer a novel way to improve treatment outcomes for liver cancer compared to traditional methods. ^{1 2 3 4 9}

Research Team

Nadine Abi-Jaoudeh, MD

Principal Investigator

UC Irvine Medical Center

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Nivolumab Injectable Product (PD-1 Inhibitor)
• Opdivo Injectable Product or Keytruda Injectable Product (PD-1 Inhibitor)
• Trans-arterial tirapazamine embolization (Combination Product)

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.

Participant Groups

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 Japan, Canada for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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, 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]

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]

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]

References

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

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

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

Tremelimumab. [2023]

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

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. [2018]

4. England 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. [2021]

5. England 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. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

7. Switzerland 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. [2021]

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

Anti-Programmed death-1 therapy in advanced hepatocellular carcinoma: A real-world experience. [2021]

9. England pubmed.ncbi.nlm.nih.gov

PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma. [2023]