Radiotherapy + Immunotherapy for Liver Cancer

Overseen By Jamese Johnson

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mary Feng, MD

Must be taking: Antivirals

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disorders, Organ transplant, 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: 7

Duration: Up to 24 months

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for liver cancer that has spread and worsened. It combines targeted radiation therapy with the drugs durvalumab and tremelimumab, both of which may help the immune system fight cancer. The goal is to determine if these treatments can more effectively slow or stop cancer growth compared to radiation alone. The trial seeks patients whose liver cancer has worsened after previous immunotherapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive medication, you must stop it at least 14 days before starting the trial, with some exceptions like certain steroids. It's best to discuss your specific medications with the study team.

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

Research shows that using hypofractionated radiation therapy with the drug durvalumab is generally safe. In earlier studies, most patients did not experience serious side effects. Common side effects included tiredness and skin reactions, which were manageable.

Adding another drug, tremelimumab, maintains similar safety levels, though there might be a slightly higher chance of mild side effects like diarrhea or a rash. These effects are usually not serious and can be treated.

Durvalumab and tremelimumab enhance the immune system's ability to fight cancer. While these treatments are still under investigation, earlier studies show promising safety results, particularly for liver cancer that has worsened after standard treatments.

Current evidence suggests that the treatment combinations being tested are safe, with most side effects being mild and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for liver cancer because they combine innovative therapies to potentially enhance effectiveness. Unlike traditional treatments that may rely solely on chemotherapy or surgery, this approach uses hypofractionated radiation therapy together with immunotherapy drugs, durvalumab and tremelimumab. Durvalumab and tremelimumab work by boosting the body's immune system to better recognize and attack cancer cells. This combination aims to not only target the tumor directly with radiation but also strengthen the body's natural defenses, offering a promising new strategy for tackling liver cancer.

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

Studies have shown that a special type of radiation therapy, called hypofractionated radiation, followed by the drug durvalumab, can effectively treat advanced liver cancer. This combination boosts the body's immune system to fight cancer cells. In this trial, some participants will receive hypofractionated radiation and durvalumab.

Another group will receive an additional drug, tremelimumab, alongside hypofractionated radiation and durvalumab. Research suggests that adding tremelimumab might further strengthen the immune response, potentially slowing or stopping cancer growth. Previous patients who received this combination showed promising results in controlling cancer progression. These treatments block signals that allow cancer to hide from the immune system, making it easier for the body to attack cancer cells. ^{1 3 4 5 6}

Who Is on the Research Team?

Mary Feng, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults with advanced liver cancer that has worsened after PD-1 inhibitor therapy. They must have manageable hepatitis B, good organ function, no history of certain autoimmune diseases or immunodeficiencies, and not be on conflicting medications or treatments. Participants need to agree to use contraception and have a life expectancy of at least 12 weeks.

Inclusion Criteria

I am on antiviral therapy for hepatitis B with low viral load.

My liver is functioning well enough, meeting specific health criteria.

My liver disease diagnosis was confirmed through imaging, meeting AASLD standards.

Exclusion Criteria

I haven't had major surgery or cancer treatment recently and have no ongoing side effects.

I have previously been treated with CTLA-4 or PD-L1 inhibitors, or have had an organ transplant.

I've had radiation that now makes further treatment unsafe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo standard of care hypofractionated radiation therapy over 5 fractions once daily for 5 days

1 week

5 visits (in-person)

Treatment

Patients receive durvalumab with or without tremelimumab intravenously. Treatment repeats every 28 days for up to 2 years

Up to 24 months

1 visit every 28 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 2 months

1 visit every 2 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Hypofractionated Radiation Therapy
• Tremelimumab

Trial Overview The study tests if hypofractionated radiation followed by durvalumab alone or with tremelimumab improves outcomes in liver cancer patients who've progressed on PD-1 inhibitors. It's seeing whether these drugs can boost the immune system's response against cancer when given after targeted high-dose radiation therapy.

How Is the Trial Designed?

Group I: Arm II (hypofractionated RT, durvalumab, tremelimumab) Experimental Treatment 3 Interventions

Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who complete the first dose of tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or other clinical response without progression for at least 6 cycles or 6 months on treatment, whichever is shorter, and subsequently have evidence of progressive disease during the durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next scheduled cycle of treatment with durvalumab per physician discretion.

Group II: Arm I (hypofractionated RT, durvalumab) Experimental Treatment 2 Interventions

Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

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?

Mary Feng, MD

Lead Sponsor

Trials

1

Recruited

20+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

In a phase 2 trial involving 90 patients with non-small-cell lung cancer resistant to PD-1/PD-L1 therapy, the combination of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) with radiotherapy did not show improved overall response rates compared to the therapy alone, leading to the trial's early termination due to futility.

The most common serious adverse events were manageable, but one patient in the low-dose radiotherapy group died from respiratory failure potentially related to the treatment, highlighting the need for careful monitoring in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Schoenfeld, JD., Giobbie-Hurder, A., Ranasinghe, S., 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, 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 study involving 10 patients receiving palliative radiotherapy (RT) combined with durvalumab, the treatment was well tolerated, with only 50% experiencing mild to moderate adverse events, primarily G2 mucositis, and no severe adverse events reported.

The treatment showed promising efficacy, with a 60% objective response rate in evaluable lesions and a significant decrease in tumor growth rate after RT, indicating that durvalumab combined with RT may effectively reduce tumor size in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Levy, A., Massard, C., Soria, JC., et al.[2022]

In the Phase 3 PACIFIC study involving 713 patients with unresectable stage III non-small-cell lung cancer (NSCLC), the anti-PD-L1 agent durvalumab significantly improved median progression-free survival (17.2 months vs. 5.6 months for placebo) and overall survival (not reached vs. 28.7 months for placebo).

While durvalumab showed a slight increase in grade 3 or 4 toxicity (30.5% vs. 26.1% for placebo), its efficacy in prolonging survival justifies its use, leading to its licensing for this treatment setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®▼, AstraZeneca UK Limited). Patel, P., Alrifai, D., McDonald, F., et al.[2023]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In the phase 3 MYSTIC study involving 488 treatment-naïve patients with metastatic non-small-cell lung cancer, durvalumab alone or in combination with tremelimumab showed significant improvements in patient-reported outcomes (PROs) compared to chemotherapy, particularly in reducing fatigue and appetite loss.

Patients receiving durvalumab-containing treatments experienced a longer time to deterioration in quality of life and physical functioning, indicating that these treatments may help maintain better overall well-being without negatively impacting quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Garon, EB., Cho, BC., Reinmuth, N., et al.[2022]

In a pilot trial involving 24 patients with locally advanced unresectable hepatocellular carcinoma (HCC), the combination of Y90-radioembolization and durvalumab showed promising efficacy, with a median time to progression of 15.2 months and an overall response rate of 83.3%.

The treatment was generally safe, with 47.8% of patients experiencing any-grade treatment-related adverse events, but only 8.7% had grade 3 adverse events, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma. Lee, YB., Nam, JY., Cho, EJ., et al.[2023]

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

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]

Citations

1. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT04430452

Hypofractionated Radiotherapy Followed by Durvalumab ... This phase II trial studies how well standard of care hypofractionated radiation therapy followed by durvalumab with or without tremelimumab works in treating ...

2. asco.org asco.org/abstracts-presentations/ABSTRACT392630

Phase II trial of durvalumab (MEDI4736) with/without ... Phase II trial of durvalumab (MEDI4736) with/without tremelimumab for advanced hepatocellular carcinoma after palliative hypofractionated radiotherapy.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT07027436

Radiation Therapy Followed by Durvalumab (MEDI4736) ... The objectives of this study is to estimate the biological activity of combination chemotherapy and radiation versus radiation alone in patients with Hepato ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10894375/

Phase I/II study to evaluate consolidative hypofractionated ... The goal of this study is to evaluate the safety and efficacy of combining consolidative hypofractionated radiation therapy (hfRT) using stereotactic body ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03482102

Study Details | NCT03482102 | Durvalumab (MEDI4736) ... This research study is studying a combination of drugs as a possible treatment for Hepatocellular Carcinoma or Biliary Tract Cancer. The interventions involved ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03801902

NCT03801902 | Testing the Safety of Adding Either ... This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation ...