Radioembolization + Immunotherapy for Bile Duct Cancer

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Immunosuppressants, Anticancer vaccines

Disqualifiers: Autoimmune disorders, Uncontrolled hypertension, HIV, others

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

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 24 months

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety and side effects of yttrium-90 (Y90) radioembolization combined with immunotherapy drugs tremelimumab and durvalumab in treating patients with intrahepatic cholangiocarcinoma (cancer of the bile ducts in the liver) that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable) who are not candidates for curative therapy or that has spread from where it first started (primary side) to multiple other places in the body (oligo-metastatic). Cholangiocarcinoma is a rare but aggressive cancer with limited curative options outside of surgery. Immunotherapy has shown modest benefit in hepatobiliary (liver, bile ducts, and gallbladder) cancers including cholangiocarcinoma. Radioembolization is a type of radiation therapy used to treat liver cancer that is advanced or has come back where tiny beads that hold the radioactive substance (radioisotope) yttrium Y90 are injected into or near the hepatic artery (the main blood vessel that carries blood to the liver). The beads collect in the tumor and the Y90 gives off radiation. This destroys the blood vessels that the tumor needs to grow and kills the tumor cells. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving Y90 radioembolization in combination with tremelimumab and durvalumab immunotherapy may be safe and beneficial in treating patients with locally advanced, unresectable or oligo-metastatic intrahepatic cholangiocarcinoma who are not candidates for curative therapy.

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, you cannot use immunosuppressive medications within 14 days before joining the trial, except for certain low-dose steroids and local steroid treatments.

What data supports the effectiveness of the drug combination of durvalumab and tremelimumab for bile duct cancer?

The combination of durvalumab and tremelimumab has been approved for use in other cancers, such as unresectable hepatocellular carcinoma, where it showed improved survival rates compared to another treatment. This suggests potential effectiveness in treating bile duct cancer as well. ^{1 2 3 4 5}

Is the combination of radioembolization and immunotherapy safe for humans?

The combination of tremelimumab and durvalumab has been studied in various cancers, showing common side effects like rash, fatigue, and diarrhea. In a study for gastric cancer, serious side effects were mostly related to chemotherapy, not the immunotherapy drugs. Overall, these treatments have been used safely in humans, but side effects can occur. ^{2 4 6 7 8}

How is the drug combination of durvalumab and tremelimumab unique for bile duct cancer?

The combination of durvalumab and tremelimumab is unique for bile duct cancer because it uses two immune checkpoint inhibitors to enhance the body's immune response against cancer cells, which is different from traditional chemotherapy. This approach is novel as it targets specific pathways (PD-L1 and CTLA4) to boost the immune system's ability to fight cancer. ^{1 3 9 10 11}

Research Team

Umair Majeed, MBBS, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for adults over 18 with locally advanced, unresectable intrahepatic cholangiocarcinoma who can't have curative therapy. They should be in good physical condition (ECOG PS 0 or 1), not pregnant, and without severe concurrent diseases or a history of multiple treatments for this cancer.

Inclusion Criteria

International normalized ratio (INR) =< 1.6. Note: INR prolongation due (=< 14 days prior to registration)

Platelet count >= 75,000/mm^3 (=< 14 days prior to registration)

Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 5 x ULN (=< 14 days prior to registration)

Exclusion Criteria

ALBI grade > 2

Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

I have had cancer before, but it was a different type than my current diagnosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive transarterial Y90 radioembolization and immunotherapy drugs tremelimumab and durvalumab. Cycles repeat every 28 days for up to 24 cycles.

Up to 24 months

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

24 months

Every 3 months

Treatment Details

Interventions

• Durvalumab
• Tremelimumab
• Yttrium-90 Microsphere Radioembolization

Trial Overview The trial tests Y90 radioembolization combined with two monoclonal antibodies, tremelimumab and durvalumab. It aims to see if this combination is safe and effective at killing more tumor cells in patients who cannot undergo surgery.

Participant Groups

Group I: Cohort II: (Y90, tremelimumab on day 14, cycle 1, durvalumab ) Experimental Treatment 9 Interventions

Patients receive transarterial Y90 radioembolization on day 1 of cycle 1 and receive tremelimumab IV over 1 hour on day 14 of cycle 1 and durvalumab IV over 1 hour on day 14 of each cycle. Cycles repeat every 42 days for cycle 1 and then every 28 days for cycles 2-24 in the absence of disease progression or unacceptable toxicity. Patients also undergo mapping angiography during screening, as well as CT and MRI or PET/CT during screening and on study. Patients also undergo blood sample collection throughout the trial and may undergo tumor biopsy during screening and on study.

Group II: Cohort I: (Y90, tremelimumab on day 1, cycle 1, durvalumab) Experimental Treatment 9 Interventions

Patients receive transarterial Y90 radioembolization and tremelimumab IV over 1 hour on day 1 of cycle 1 and durvalumab IV over 1 hour on day 1 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo mapping angiography during screening as well as CT and MRI or PET/CT during screening and on study. Patients also undergo blood sample collection throughout the trial and may undergo tumor biopsy during screening and on study.

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

In a phase Ib trial involving 34 patients with metastatic pancreatic cancer, tremelimumab combined with gemcitabine showed a good safety profile, with no dose-limiting toxicities observed even at the maximum dose of 15 mg/kg.

The combination treatment resulted in a median overall survival of 7.4 months, with two patients achieving a partial response, indicating potential efficacy that supports further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Aglietta, M., Barone, C., Sawyer, MB., et al.[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]

Tremelimumab shows linear pharmacokinetics with a two-compartment model, and its clearance varies depending on whether it is used as monotherapy or in combination with durvalumab, with a 16% increase in clearance for monotherapy and a 17% decrease for combination therapy over one year.

Factors like higher body weight and lower albumin levels lead to higher drug clearance, but no dosage adjustments are needed, as a flat dose of 75 mg provides similar exposure to the weight-based dosing of 1 mg/kg in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. Hwang, M., Chia, YL., Zheng, Y., et al.[2023]

In a study of 112 patients receiving durvalumab for cancer treatment, 19% experienced liver injury, which was linked to higher rates of tumor progression and mortality, indicating that liver injury may be a significant concern in this patient population.

Among the liver injury cases, 29% were classified as probable drug-induced liver injury (DILI) related to durvalumab, but these cases were generally mild and self-limited, suggesting that while monitoring for liver injury is important, severe complications are rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis. Swanson, LA., Kassab, I., Tsung, I., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

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]

Durvalumab monotherapy and the combination of durvalumab with tremelimumab showed acceptable safety profiles, with grade ≥3 treatment-related adverse events occurring in 19.0% of patients with biliary tract cancer (BTC) and 25.0% with head and neck squamous cell carcinoma (HNSCC).

The combination therapy demonstrated a higher objective response rate (ORR) of 10.8% in BTC and 20.3% in esophageal squamous cell carcinoma (ESCC), indicating potential clinical benefit for patients with advanced cancers who had disease progression after prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Doki, Y., Ueno, M., Hsu, CH., et al.[2022]

Tremelimumab, an anti-CTLA4 monoclonal antibody, enhances T cell activation and has shown promising antitumor activity in advanced melanoma and colorectal cancer, with objective response rates of about 10% and 2%, respectively.

In Phase I and II studies, tremelimumab was well tolerated, with manageable side effects, and most responses lasted over 180 days, indicating potential for durable treatment effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. Tarhini, AA., Kirkwood, JM.[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]

References

1. 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]

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

Tremelimumab: First Approval. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. [2023]

4. 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]

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

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Liver injury during durvalumab-based immunotherapy is associated with poorer patient survival: A retrospective analysis. [2023]

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

Durvalumab: First Global Approval. [2022]

8. 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]

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

Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Tremelimumab (CP-675,206): a fully human anticytotoxic T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. [2021]

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

Tremelimumab. [2023]