Combination Therapy + TACE for Liver Cancer

Overseen By Tim F Greten, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Antivirals

Must not be taking: Steroids, NSAIDs, Aspirin

Disqualifiers: HIV, CNS metastases, Hypertension, 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: 13

Duration: 6 months

27 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Most people with advanced HCC survive an average of 6 to 9 months. Researchers are evaluating a combination of treatment drugs to delay the progression of HCC; aiming to help people with HCC live longer. Objective: To study the 6-month progression-free survival in people with advanced HCC treated with bevacizumab, durvalumab, and TACE. Eligibility: Adults ages 18 and older with intermediate or advanced HCC Design: Participants will be screened with a physical exam and medical history. They will have tests to evaluate their hearts as well as blood and urine. A CT and/or MRI scans will be done during the study. If a prior tumor sample is not available; participants may undergo a biopsy. They may undergo an endoscopy of their esophagus and stomach. Participants will get the study drugs in 21-day cycles: Two treatment drugs will be injected into a vein every 3 weeks. Patients will have an interventional treatment procedure done by interventional radiology under sedation; chemotherapy beads will be infused into artery branches in the liver. Participants may have to stay in the hospital for 24 hours for observation, after this procedure. This interventional procedure may be done more than once during the study. Participants may need to repeat some of the screening tests throughout the study. Participants may have to stop taking some of their cancer treatment drugs during the study. Participants will continue on the study until their cancer progresses or until the side effects of the treatment drugs are not tolerable.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that participants may have to stop some cancer treatment drugs during the study. It's best to discuss your specific medications with the trial team.

Is the combination of Tremelimumab and Durvalumab safe for humans?

The combination of Tremelimumab and Durvalumab has been studied for safety in various cancers, including liver cancer. Common side effects include rash, fatigue, diarrhea, itching, muscle pain, and abdominal pain. Serious side effects occurred in about 32.6% of patients, which is higher than when using Durvalumab alone. ^{1 2 3 4 5}

What makes the combination therapy with Bevacizumab, Durvalumab, and Tremelimumab unique for liver cancer?

This combination therapy is unique because it uses a mix of drugs that target different aspects of cancer growth and immune response, potentially offering a more comprehensive approach to treating liver cancer compared to standard treatments. ^{6 7 8 9 10}

Research Team

Tim F Greten, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with advanced liver cancer (Hepatocellular Carcinoma or Biliary Tract Carcinoma) who've tried standard treatments without success, or can't tolerate them. They should be in good physical condition (ECOG 0-1), have acceptable organ function and blood counts, and no serious heart issues. Women of childbearing age and men must use contraception during the trial.

Inclusion Criteria

My liver cancer is classified as either BCLC stage C or B.

My condition cannot be cured with surgery, ablation, or a liver transplant.

I have recovered from side effects of my previous cancer treatment.

Exclusion Criteria

My blood pressure is not well-controlled, even with medication.

I do not have HIV.

I am on long-term steroids or other drugs that weaken my immune system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive durvalumab, bevacizumab, tremelimumab, and TACE in 21-day cycles

6 months

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Every 9 weeks (in-person)

Open-label extension (optional)

Participants may continue treatment until progression or unbearable toxicity

Treatment Details

Interventions

• Bevacizumab
• Doxorubicin-Eluting Beads
• Durvalumab
• TACE
• Tremelimumab

Trial Overview The trial tests a combination therapy for liver cancer: Durvalumab, Bevacizumab, Tremelimumab injections every three weeks plus TACE - a procedure where chemotherapy beads are delivered directly to the liver tumor. The goal is to see if this combo helps patients live longer without their cancer getting worse.

Participant Groups

Group I: 3/Arm 3 Experimental Treatment 3 Interventions

Durvalumab, low-dose bevacizumab, and tremelimumab

Group II: 2/Arm 2 Experimental Treatment 5 Interventions

Durvalumab, bevacizumab, tremelimumab and TACE

Group III: 1/Arm 1 Experimental Treatment 3 Interventions

Durvalumab, bevacizumab and tremelimumab

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

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

The FDA approved tremelimumab in combination with durvalumab for treating unresectable hepatocellular carcinoma based on the HIMALAYA study, which showed a significant improvement in overall survival (OS) compared to sorafenib, with a median OS of 16.4 months versus 13.8 months.

Common adverse reactions in patients receiving the combination treatment included rash, fatigue, diarrhea, and abdominal pain, occurring in 20% or more of patients, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. Patel, TH., Brewer, JR., Fan, J., et al.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

The DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

In a 24-week study involving 75 rheumatoid arthritis patients, tacrolimus (TAC) combined with methotrexate (MTX) was found to be non-inferior in efficacy compared to leflunomide (LEF) combined with MTX, indicating that TAC is an effective alternative treatment.

The safety profile of TAC was better than LEF, with fewer adverse events reported (49 in TAC group vs. 66 in LEF group), and lower instances of liver enzyme elevation (transaminitis) in the TAC group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. Shin, K., Baek, HJ., Kang, YM., et al.[2020]

References

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

Tremelimumab: First Approval. [2023]

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

FDA Approval Summary: Tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

5. England pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

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

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. [2020]

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

Ab initio Everolimus-based Versus Standard Calcineurin Inhibitor Immunosuppression Regimen in Liver Transplant Recipients. [2021]

9. Spain pubmed.ncbi.nlm.nih.gov

Everolimus versus mycophenolate mofetil in liver transplantation: every improvement in renal function matters. [2022]

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

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report. [2019]