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

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for advanced bile duct cancer that cannot be removed with surgery. It combines radioembolization, where tiny radioactive beads target liver tumors, with the immunotherapy drugs tremelimumab and durvalumab, which help the immune system fight cancer. The study assesses the safety and side effects of this combination. Suitable candidates for this trial have intrahepatic cholangiocarcinoma (bile duct cancer in the liver) that has spread and cannot be treated with surgery. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new 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.

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

Studies are exploring the safety of combining yttrium-90 (Y90) radioembolization with two immunotherapy drugs, durvalumab and tremelimumab, for certain liver cancers. Patients who received Y90 radioembolization in the past generally tolerated it well. Common side effects include fatigue and minor changes in liver function, with serious issues being rare.

Research has shown that durvalumab and tremelimumab are also usually well-tolerated. Some individuals have experienced fatigue and skin rashes. These drugs are already used for other conditions, suggesting they are relatively safe.

Since this trial is in its early stages (Phase 1), the main focus is on understanding safety and side effects. Detailed safety data is limited, but early results are promising. The goal of combining these treatments is to harness the benefits of both radioembolization and immunotherapy, potentially offering a safe option for challenging cases of bile duct cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using radioembolization combined with immunotherapy for bile duct cancer because it offers a unique dual approach. Unlike standard treatments like chemotherapy or surgery, this method uses transarterial Y90 radioembolization to deliver targeted radiation directly to the tumor, minimizing damage to surrounding tissue. Additionally, the inclusion of immunotherapy drugs, Durvalumab and Tremelimumab, aims to enhance the body's immune response against cancer cells. This combination could potentially improve outcomes by attacking the cancer on multiple fronts, offering hope for more effective treatment with potentially fewer side effects.

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

Research shows that combining a special type of radiation treatment with certain immune-boosting drugs may help treat liver-related cancers. In this trial, one group of participants will receive yttrium-90 radioembolization, a radiation treatment that directly targets liver tumors to shrink them, along with durvalumab and tremelimumab on specific days of the treatment cycle. Another group will receive the same treatments but with a different schedule for administering tremelimumab. The immune-boosting drugs, durvalumab and tremelimumab, help the body's immune system better recognize and fight cancer cells. Previous studies have shown some benefits in treating similar liver and bile duct cancers with these methods. These early findings offer hope that this combination could help patients with advanced bile duct cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Umair Majeed, MBBS, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06058663

Study Details | NCT06058663 | Radioembolization With ... This phase I trial tests the safety and side effects of yttrium-90 (Y90) radioembolization combined with immunotherapy drugs tremelimumab and durvalumab in ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04605731

Durvalumab and Tremelimumab After Radioembolization ... This phase Ib trial investigates the side effects of durvalumab and tremelimumab after radioembolization (radiation particles against liver tumors)

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37459133/

A Phase I/IIa Trial of Yttrium-90 Radioembolization in ... This phase I/IIa pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) ...

4. dana-farber.org dana-farber.org/clinical-trials/22-401

A Phase 1 Neoadjuvant Trial of Selective Internal Yttrium ... The goal of this research study is to evaluate the safety and tolerability of tremelimumab and durvalumab with or without Selective Internal Yttrium-90

5. theranostictrials.org theranostictrials.org/studies/cl74bp9il0290ajjfhjzb2qm5

Hepatocellular/Liver (GI) The goal of this research study is to evaluate the safety and tolerability of tremelimumab and durvalumab with or without Selective Internal Yttrium-90 ...

6. cholangiocarcinoma.org cholangiocarcinoma.org/a-single-arm-phase-2-study-of-y-90-sirt-in-combination-with-durvalumab-medi-4736-and-gemcitabine-cisplatin-in-locally-advanced-unresectable-or-metastatic-intrahepatic-cholangiocarcinoma/

A single arm phase 2 study of Y-90 SIRT in combination ... This trial evaluates a combination of interventions (chemotherapy, immunotherapy, and radiation) as a potential new treatment for advanced ...