Immunotherapy for Liver Cancer

(HIMALAYA Trial)

Not currently recruiting at 189 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Disqualifiers: Hepatic encephalopathy, Ascites, Portal vein thrombosis, GI bleeding, Co-infections

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 8

Duration: Up to 46 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for liver cancer that cannot be surgically removed. It aims to determine the effectiveness of durvalumab (an immunotherapy drug) alone and in combination with tremelimumab (another immunotherapy drug) compared to sorafenib in treating liver cancer. The trial seeks participants with doctor-confirmed liver cancer who have not received prior drug treatments and meet specific liver function and activity level criteria. Participants should not have conditions such as liver-related brain issues or recent severe bleeding. The goal is to improve treatment options for those living with liver cancer. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that durvalumab is generally safe for people. One study found it can help manage liver cancer with careful monitoring. However, combining durvalumab with other chemotherapy drugs increases the risk of liver damage, making the liver more susceptible to harm.

For the combination of durvalumab and tremelimumab, studies have highlighted important safety points. One study found the combination to be generally safe, with most side effects manageable. The most common issues were fatigue and some changes in liver function.

Overall, researchers are studying these treatments to determine their effectiveness and safety for a broader population. It is important to consult a doctor to understand the specific risks and benefits based on individual health conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Durvalumab and Tremelimumab for liver cancer because they represent a novel approach in immunotherapy. Unlike traditional treatments like Sorafenib, which targets cancer cell growth, these drugs enhance the body's immune response against cancer cells. Durvalumab blocks the PD-L1 protein, preventing cancer cells from evading the immune system. Tremelimumab, on the other hand, targets the CTLA-4 protein, further stimulating immune activity. Together, they offer a promising alternative that could result in a more robust and sustained attack on liver cancer cells.

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

Research shows that durvalumab, a type of immune therapy, yields promising results for liver cancer. In this trial, some participants will receive durvalumab alone, while others will receive it in combination with tremelimumab. Studies have found that durvalumab can safely manage the disease and improve outcomes for patients with hepatocellular carcinoma (HCC). In some trials, combining durvalumab with tremelimumab led to remarkable survival rates, with one in five patients living for five years. The FDA has approved this combination for treating liver cancer that cannot be removed by surgery, indicating its effectiveness in earlier studies. These findings suggest this treatment has strong potential for managing liver cancer. ^{3 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced liver cancer (Hepatocellular Carcinoma) who haven't had systemic therapy before and can't have targeted local treatments. They should be in relatively good health (Child-Pugh A, ECOG 0 or 1). People with serious fluid buildup in the abdomen, major blood vessel blockage by the tumor, certain viral infections, recent brain issues related to liver disease, or a history of significant GI bleeding can't join.

Inclusion Criteria

My liver cancer diagnosis was confirmed through tissue examination.

My liver function is good.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

HBV and HVC co-infection, or HBV and Hep D co-infection

I have not had brain function issues due to liver disease in the last year.

I have a blood clot in the main vein of my liver caused by cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab and tremelimumab combination therapy or durvalumab monotherapy versus sorafenib

Up to 46 months

Every 8 weeks for the first 48 weeks, then every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Survival Follow-up

Participants who discontinue treatment due to disease progression enter survival follow-up

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Tremelimumab

Trial Overview The study compares three approaches: one group gets Durvalumab plus Tremelimumab; another gets just Durvalumab; and a third receives Sorafenib. It's designed to see which treatment is better as a first-line option for unresectable Hepatocellular Carcinoma.

How Is the Trial Designed?

Group I: Arm 3 Experimental Treatment 2 Interventions

Durvalumab in combination with tremelimumab (Regimen 2)

Group II: Arm 2 Experimental Treatment 2 Interventions

Durvalumab in combination with tremelimumab (Regimen 1)

Group III: Arm 1 Experimental Treatment 1 Intervention

Durvalumab

Group IV: Arm 4 Active Control 1 Intervention

Sorafenib

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?

AstraZeneca

Lead 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

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]

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]

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]

The combination of tremelimumab and durvalumab (T300 + D) showed the highest overall survival rate (18.7 months) and objective response rate (24.0%) among patients with unresectable hepatocellular carcinoma, indicating its potential as an effective treatment option.

All treatment regimens were generally well-tolerated, but T300 + D had the most favorable safety profile, with a significant association between early CD8+ lymphocyte expansion and treatment response, suggesting a promising mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Kelley, RK., Sangro, B., Harris, W., 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]

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]

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 the phase III HIMALAYA trial, patients with inoperable hepatocellular carcinoma who received a single dose of tremelimumab combined with monthly durvalumab showed improved overall survival compared to those treated with sorafenib.

This suggests that the combination therapy may be a more effective first-line treatment option for this type of liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Immunotherapy Makes Strides against HCC. [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]

The combination of durvalumab and tremelimumab was studied in 19 articles involving 2052 patients with solid tumors, showing some benefits over traditional chemotherapy in certain tumor types.

However, this combination did not consistently outperform durvalumab alone, indicating that while it may have potential, further research with larger and better-designed studies is needed to clarify its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review. Arru, C., De Miglio, MR., Cossu, A., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05027425

Study Details | NCT05027425 | Durvalumab (MEDI4736) ... Immunotherapy can safely downstage patients and achieve durable systemic disease control to improve clinical outcomes in HCC patients undergoing liver ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.TPS630

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. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2024/imfinzi-plus-imjudo-demonstrated-unprecedented-overall-survival-alc-with-one-in-five-patients-surviving-five-years-himalaya-phase-iii-trial.html

Imfinzi plus Imjudo demonstrated unprecedented overall ... Imfinzi plus Imjudo demonstrated unprecedented overall survival in advanced liver cancer with one in five patients surviving five years in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6738201/

Immuno-Oncology Therapy for Hepatocellular Carcinoma Although only 30 patients were evaluated for safety and efficacy, the ORR per RECIST 1.1 was 53.3%, the disease control rate was 90.0%, and 6.7% ...

5. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/520275

Study of Tremelimumab and Durvalumab ... - Carebox Connect It can be used to predict the prognosis of patients with liver cirrhosis and hepatocellular carcinoma, and has been shown to be more accurate ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06911255

Safety and Efficacy of Tremelimumab+Durvalumab ... The purpose of this clinical trial is to evaluate the safety and efficacy of tremelimumab + durvalumab administered concurrently with transarterial ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9637844/

Liver injury during durvalumab-based immunotherapy is ... Durvalumab given in combination with cytotoxic chemotherapy resulted in the highest rate of liver injury (71.4%% vs. 29.7%) compared to when it was given alone ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5569690/

Safety and Efficacy of Durvalumab (MEDI4736), an Anti ... To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), ...