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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of drug therapies to slow the progression of advanced liver cancer, known as hepatocellular carcinoma (HCC). The researchers aim to determine if bevacizumab, durvalumab, tremelimumab, and TACE (a procedure delivering chemotherapy directly to the liver) can extend patients' lives without worsening their cancer. Individuals with intermediate or advanced HCC who are not eligible for surgery or a liver transplant might be suitable candidates. Participants will receive treatments every three weeks, with doctors monitoring their cancer and overall health throughout the trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

Research has shown that using durvalumab, bevacizumab, and tremelimumab together can provide additional benefits for people with liver cancer. In earlier studies, most patients tolerated this combination well, with side effects that were usually manageable. Common side effects included fatigue, loss of appetite, and high blood pressure.

When durvalumab and bevacizumab were used with a procedure called transarterial chemoembolization (TACE), studies found that this method reduced the risk of disease progression or death by 23%. The side effects were similar to those from the individual treatments.

Overall, while some side effects may occur, these treatments have generally been safe for patients in past studies. Participants in the trial will be closely monitored to help manage any side effects that may arise. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for liver cancer because it brings together a trio of drugs—Durvalumab, Bevacizumab, and Tremelimumab—that work in concert to enhance the body's immune response against cancer cells. Unlike standard treatments like surgery, chemotherapy, or radiofrequency ablation, this approach includes immunotherapy agents that help the immune system recognize and attack cancer cells more effectively. Additionally, one of the arms in the trial combines these drugs with TACE (Transarterial Chemoembolization), which directly targets the tumor's blood supply. This multi-faceted strategy could offer a more comprehensive attack on liver cancer, potentially improving outcomes for patients.

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

Research shows that combining the drugs durvalumab, bevacizumab, and tremelimumab yields promising results for treating liver cancer. This trial will test this combination in one arm. Another arm will evaluate durvalumab, low-dose bevacizumab, and tremelimumab. Additionally, a separate arm will assess these drugs combined with a procedure called TACE, which cuts off the tumor's blood supply. Studies have found that adding these drugs to TACE reduced the risk of cancer progression or death by 23%, allowing patients to live longer without their cancer worsening. The initial results are hopeful, but further research is needed to confirm these benefits. ^{1 6 7 8 9}

Who Is on the Research Team?

Tim F Greten, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK599983/

Tremelimumab (Imjudo) in Combination With Durvalumab ... ... tremelimumab in combination with durvalumab resulted in added clinical benefit in adult patients with unresectable hepatocellular carcinoma. The HIMALAYA ...

2. imfinzihcp.com imfinzihcp.com/hcc/unresectable/efficacy.html

Efficacy Outcomes by baseline liver function in patients with unresectable hepatocellular carcinoma treated with tremelimumab and durvalumab in the phase 3 HIMALAYA ...

3. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2100070

Tremelimumab plus Durvalumab in Unresectable ... STRIDE significantly improved overall survival versus sorafenib. Durvalumab monotherapy was noninferior to sorafenib for patients with unresectable ...

4. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2023/imfinzi-durvalumab-plus-bevacizumab-met-primary-endpoint-for-progression-free-survival-in-liver-cancer-eligible-for-embolization-in-emerald-1-phase-iii-trial-11092023.html

IMFINZI® (durvalumab) plus bevacizumab met primary ... IMFINZI (durvalumab) plus bevacizumab met primary endpoint for progression-free survival in liver cancer eligible for embolization in EMERALD-1 Phase III trial.

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534%2824%2900049-8/fulltext

Four-year overall survival update from the phase III ... Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma

6. asco.org asco.org/abstracts-presentations/ABSTRACT400980

A phase II study of tremelimumab, durvalumab, and ... Safety and efficacy of durvalumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from the phase 2 study 22 (NCT02519348). First Author ...

7. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effects-of-durvalumab-tremelimumab-and-bevacizumab-in-patients-with-advanced-liver-cancer/

Study on the Safety and Effects of Durvalumab ... This study examines the safety and effects of Durvalumab, Tremelimumab, and Bevacizumab in the treatment of advanced Hepatocellular ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.TPS638

Durvalumab and tremelimumab for hepatocellular ... This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of ...

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2022/761289Orig1s000MultidisciplineR.pdf

761289Orig1s000 - accessdata.fda.gov The data supporting FDA's assessment of the safety of tremelimumab in combination with durvalumab is based primarily on the HIMALAYA trial, a global ...