SIRT + Immunotherapy for Liver Cancer

Overseen By Anuj Patel, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jiping Wang, MD, PhD

Must not be taking: Immunosuppressants, Investigational agents

Disqualifiers: Autoimmune disorders, Organ transplant, 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: Unknown

20 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are using immunosuppressive medication within 14 days before the trial, or if you have received a live vaccine within 30 days before the trial.

What data supports the effectiveness of the treatment SIRT + Immunotherapy for Liver Cancer?

The combination of tremelimumab and durvalumab has been shown to improve overall survival in patients with unresectable hepatocellular carcinoma (a type of liver cancer) compared to another treatment, sorafenib, as demonstrated in the HIMALAYA study. This combination has also been approved for use in this condition by the FDA, indicating its effectiveness. ^{1 2 3 4 5}

Is the combination of SIRT, Durvalumab, and Tremelimumab safe for humans?

The combination of Durvalumab and Tremelimumab has been studied for safety in various cancers, showing that serious side effects can occur, such as reduced appetite, diarrhea, rash, fatigue, and abdominal pain. In some studies, a significant number of patients experienced severe adverse events, but these were generally considered manageable. ^{1 2 5 6 7}

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

The combination of durvalumab and tremelimumab is unique for liver cancer because it targets the immune system to fight cancer cells, using two different mechanisms: durvalumab blocks PD-L1, and tremelimumab blocks CTLA-4, both of which help the immune system attack cancer more effectively. This combination has shown improved survival rates compared to the standard treatment sorafenib for patients with unresectable hepatocellular carcinoma. ^{1 2 5 8 9}

What is the purpose of this trial?

The goal of this research study is to evaluate the safety and tolerability of tremelimumab and durvalumab with or without Selective Internal Yttrium-90 Radioembolization (SIRT) in participants with resectable hepatocellular carcinoma (HCC) who will undergo liver surgery. The names of the interventions involved in this study are: * Durvalumab (a type of immunotherapy) * Tremelimumab (a type of immunotherapy) * Selective Internal Yttrium-90 Radioembolization (SIRT) (a type of radiation microsphere bead)

Research Team

Jiping Wang, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with resectable hepatocellular carcinoma (HCC) who haven't been treated for it before can join this trial. They should have a certain level of liver function, no history of other cancers affecting the study, and be able to understand and sign consent. Women must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

Ability to understand and sign a written informed consent document

I am fully active and can carry on all pre-disease activities without restriction.

My body weight is over 30 kg.

Exclusion Criteria

I need nutrition through an IV including fats.

Participants receiving any other investigational agents

I haven't had major surgery or a significant injury in the last 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive Durvalumab and Tremelimumab, with or without SIRT, followed by surgery

7-8 weeks

Multiple visits for treatment administration and surgery

Adjuvant Treatment

Participants receive Durvalumab postoperatively for up to 13 cycles

12 months

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety, effectiveness, and survival outcomes

up to 3 years

Treatment Details

Interventions

• Durvalumab
• Selective Internal Yttrium-90 Radioembolization (SIRT)
• Tremelimumab

Trial Overview The trial is testing the safety of combining two immunotherapies, Tremelimumab and Durvalumab, with or without SIRT (a type of targeted radiation therapy), in patients planning to undergo liver surgery for HCC.

Participant Groups

Group I: Durvalumab + Tremelimumab + SIRT (Arm B) Experimental Treatment 3 Interventions

-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 3 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 31 of 28 Day Cycle: Pre-determined dose of Durvalumab * Day 1 of 28 Day Cycle: Yttrium-90 * Participants will undergo surgery on Day 52 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab

Group II: Durvalumab + Tremelimumab (Arm A) Experimental Treatment 2 Interventions

-Participants will be randomized into the treatment group in a 1:1 ratio and will receive interventions as outlined: Neoadjuvant Treatment: * Cycle 1: * Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab and Tremelimumab * Day 28 of 28 Day cycle: Pre-determined dose of Durvalumab * Participants will undergo surgery on day 49 of Cycle 1. Surgery will be performed per institutional standard of care. Adjuvant Treatment: --Cycles 1 (28 days postoperatively) - 13: ---Day 1 of 28 Day Cycle: Pre-determined dose of Durvalumab

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?

Jiping Wang, MD, PhD

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

Sirtex Medical

Industry Sponsor

Trials

30

Recruited

4,300+

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]

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 single-dose regimen of 300 mg tremelimumab combined with durvalumab (STRIDE) shows a favorable benefit-risk profile for patients with unresectable hepatocellular carcinoma (uHCC), as demonstrated in phase I/II and phase III studies.

Higher exposure to tremelimumab is associated with longer overall survival in patients, with those having minimum serum drug concentrations above the median living significantly longer (18.99 months) compared to those below the median (10.97 months), although this relationship may be influenced by other patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma. Song, X., Kelley, RK., Khan, AA., et al.[2023]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., 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]

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]

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]

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. Ireland 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). [2023]

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

Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma. [2023]

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

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

6. 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]

7. 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]

8. 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]

9. 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]