Immunotherapy Combinations for Advanced Liver Cancer

(MORPHEUS-LIVER Trial)

Recruiting at 37 trial locations

Overseen By Reference Study ID Number: GO42216 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hoffmann-La Roche

Must not be taking: Anticoagulants, NSAIDs, Immunosuppressants, others

Disqualifiers: Hypertension, Autoimmune disease, CNS metastases, 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

518 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it does exclude participants who are on certain medications like high-dose aspirin, full-dose anticoagulants, or chronic NSAIDs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Atezolizumab and Bevacizumab for advanced liver cancer?

The combination of Atezolizumab and Bevacizumab has been shown to be effective for advanced liver cancer, as demonstrated in the IMbrave150 study, which reported improved survival rates compared to the previous standard treatment, sorafenib. This combination is now considered the new standard of care for patients with unresectable hepatocellular carcinoma (HCC). ^{1 2 3 4 5}

Is the combination of atezolizumab and bevacizumab safe for humans?

The combination of atezolizumab and bevacizumab has been used as a treatment for advanced liver cancer and is generally considered safe, but it can cause side effects ranging from mild skin rashes to more serious conditions like myocarditis (inflammation of the heart) and transverse myelitis (inflammation of the spinal cord). ^{1 6 7 8 9}

How is the drug combination of Atezolizumab and Tiragolumab unique for advanced liver cancer?

The combination of Atezolizumab and Tiragolumab is unique because it involves two immunotherapy drugs that work together to enhance the body's immune response against cancer cells, offering a novel approach compared to traditional treatments like sorafenib. While Atezolizumab is already used in combination with bevacizumab for liver cancer, the addition of Tiragolumab could provide a new option for patients by potentially improving treatment effectiveness. ^{5 10 11 12 13}

What is the purpose of this trial?

This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with advanced liver cancers. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, modify the participant population, or introduce additional cohorts of participants with other types of advanced primary liver cancer. Cohort 1 will enroll participants with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for their disease. Eligible participants will initially be randomly assigned to one of several treatment arms (Stage 1). Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to receive treatment with a different treatment combination (Stage 2). When a Stage 2 treatment combination is available, this will be introduced by amending the protocol.

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

Adults with advanced liver cancer (HCC) who haven't had systemic therapy can join this trial. They must have measurable disease, proper organ function, and no HIV or active hepatitis. Participants need to agree to use contraception and should not have a history of certain medical conditions like severe allergies or autoimmune diseases.

Inclusion Criteria

My cancer is in the early stages (Stage 1 or 2).

A sample of my tumor is available from a recent biopsy.

My cancer is in the early stage (Stage 1).

Exclusion Criteria

I have had episodes of brain confusion due to liver problems.

Eligible only for control arm

I've had liver therapy within the last 28 days or am still experiencing side effects.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Stage 1

Participants are randomly assigned to one of several treatment arms and receive treatment until unacceptable toxicity or loss of clinical benefit

Up to approximately 7-9 years

Treatment Stage 2

Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may receive treatment with a different combination

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 7-9 years

Treatment Details

Interventions

• Atezolizumab
• Bevacizumab
• Tiragolumab
• Tocilizumab

Trial Overview The study tests multiple immunotherapy combinations including RO7247669 at different doses, Bevacizumab, ADG126, Atezolizumab, Tiragolumab, Tocilizumab, TPST-1120 for effectiveness and safety in treating liver cancer. It's flexible to adapt as new treatments emerge or existing ones show minimal benefit or high toxicity.

Participant Groups

Group I: Stage 1: Tobemstomig 600 mg Q3W + Bevacizumab Experimental Treatment 2 Interventions

Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group II: Stage 1: Tobemstomig 2100 mg Q2W + Bevacizumab Experimental Treatment 3 Interventions

Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group III: Stage 1: Tobemstomig 1200 mg Q3W + Bevacizumab Experimental Treatment 2 Interventions

Participants will receive Tobemstomig plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group IV: Stage 1: Atezolizumab + Bevacizumab+ IO-108 1800 mg Q3W Experimental Treatment 1 Intervention

Participants will receive atezolizumab plus bevacizumab plus IO-108 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic andbiochemical data, local biopsy results (if available), and clinical status

Group V: Stage 1: Atezolizumab + Bevacizumab + Tocilizumab Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus tocilizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group VI: Stage 1: Atezolizumab + Bevacizumab + Tiragolumab Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus tiragolumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group VII: Stage 1: Atezolizumab + Bevacizumab + TPST-1120 Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus TPST-1120 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group VIII: Stage 1: Atezolizumab + Bevacizumab + NKT2152 Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus NKT2152 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group IX: Stage 1: Atezolizumab + Bevacizumab + IO-108 1200 mg Q3W Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus IO-108 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group X: Stage 1: Atezolizumab + Bevacizumab + ADG126 Experimental Treatment 3 Interventions

Participants will receive atezolizumab plus bevacizumab plus ADG126 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

Group XI: Stage 1: Atezolizumab + Bevacizumab Active Control 2 Interventions

Participants will receive atezolizumab plus bevacizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status.

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

NiKang Therapeutics, Inc.

Industry Sponsor

Trials

5

Recruited

1,000+

Immune-Onc Therapeutics

Industry Sponsor

Trials

5

Recruited

740+

Sanofi

Industry Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Adagene Inc

Industry Sponsor

Trials

12

Recruited

1,000+

Tempest Therapeutics

Industry Sponsor

Trials

4

Recruited

1,500+

Findings from Research

Atezolizumab, an immune checkpoint inhibitor, combined with bevacizumab, has become the new standard treatment for advanced hepatocellular carcinoma (HCC), showing improved overall and progression-free survival compared to sorafenib.

This combination therapy addresses the increasing incidence of HCC linked to obesity and non-alcoholic fatty liver disease, highlighting its importance in managing advanced cases of this cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and tolerability of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Brown, ZJ., Gregory, S., Hewitt, DB., et al.[2022]

The combination of atezolizumab (a PD-L1 inhibitor) and bevacizumab has shown unprecedented efficacy in treatment-naive patients with advanced hepatocellular carcinoma (HCC), as demonstrated in the IMbrave150 Phase III trial, which established a new standard of care.

This combination therapy outperformed sorafenib monotherapy, marking a significant advancement in treatment options for HCC after years of limited progress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. Rizzo, A., Ricci, AD., Brandi, G.[2022]

Atezolizumab combined with bevacizumab is the first approved immunotherapy for first-line treatment of unresectable hepatocellular carcinoma (HCC), showing promising efficacy and tolerability in over 80 countries.

The DEMAND study is the first phase II trial to investigate the safety and efficacy of this combination therapy in patients with intermediate-stage HCC undergoing transarterial chemoembolization (TACE), focusing on 24-month survival rates and other important health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. Ben Khaled, N., Seidensticker, M., Ricke, J., et al.[2022]

The combination of atezolizumab and bevacizumab has been shown to be effective and safe for treating patients with unresectable hepatocellular carcinoma (HCC), as demonstrated in the IMbrave150 study.

This treatment targets both the immune system (via PD-L1 inhibition) and blood vessel growth (via VEGF inhibition), offering a promising approach for patients with advanced HCC who have limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies. Liu, X., Lu, Y., Qin, S.[2021]

The CRAFITY score, developed from baseline serum alpha-fetoprotein and C-reactive protein levels, effectively predicts overall survival in patients with hepatocellular carcinoma (HCC) undergoing immunotherapy, with a significant correlation between score levels and median survival times.

Patients with a CRAFITY-low score (0 points) had the longest median overall survival of 27.6 months, while those with a CRAFITY-high score (2 points) had a median survival of only 6.4 months, indicating that this score can help guide treatment decisions and patient counseling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. Scheiner, B., Pomej, K., Kirstein, MM., et al.[2022]

Tiragolumab, a TIGIT inhibitor, shows promise in treating solid cancers, particularly non-small cell lung cancer, based on results from phase I and II trials.

The combination of tiragolumab with the PD-L1 inhibitor atezolizumab has demonstrated statistically significant efficacy in multiple solid tumors, suggesting a potential new treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tiragolumab Impresses in Multiple Trials. [2021]

The IMbrave150 study supports the use of atezolizumab and bevacizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC), indicating its efficacy in this patient population.

However, this combination therapy can lead to serious side effects, as demonstrated by a case of transverse myelitis occurring during treatment, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma. Kim, KH., Baek, YH., Kang, YW., et al.[2023]

The DEDUCTIVE trial is a phase Ib study evaluating the safety and tolerability of combining durvalumab, a PD-L1 inhibitor, with tivozanib, a VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Both durvalumab and tivozanib have shown effectiveness as single agents in HCC, but this trial aims to explore their concurrent use, particularly in treatment-naive patients and those who have progressed on other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). Mahmood, S., Li, D., Lee, A., et al.[2023]

In a phase 1b study involving 223 patients with unresectable hepatocellular carcinoma, the combination of atezolizumab and bevacizumab resulted in a significantly longer median progression-free survival of 5.6 months compared to 3.4 months for atezolizumab alone, indicating enhanced efficacy of the combination treatment.

The most common serious treatment-related adverse events included hypertension and proteinuria, with a treatment-related death rate of 3% in the combination group, suggesting that while the combination therapy is effective, it does carry some safety risks that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lee, MS., Ryoo, BY., Hsu, CH., et al.[2020]

Atezolizumab plus bevacizumab (AB) showed significantly better overall survival (OS) and progression-free survival (PFS) compared to sorafenib, with hazard ratios of 0.58 and 0.59 respectively, indicating its strong efficacy in treating advanced hepatocellular carcinoma (HCC).

When comparing AB to lenvatinib plus pembrolizumab (LP), AB was found to be insignificantly more effective for OS and similarly effective for PFS, suggesting that LP could also be a viable first-line immunotherapy option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect Comparisons via Sorafenib for the Comparative Effectiveness of Two PD-1/PD-L1 Inhibitors to Treat Advanced Hepatocellular Carcinoma Patients without Prior Systemic Therapies. Jiang, Y., Cai, D., Shi, S.[2022]

Atezolizumab combined with bevacizumab demonstrated good efficacy in treating advanced hepatocellular carcinoma (HCC), with a pooled overall response rate of 26% and a median overall survival of 14.7 months based on a review of 23 studies involving 3168 patients.

The treatment was well-tolerated, with 83% of patients experiencing any grade adverse events, and 30% experiencing grade 3 or higher adverse events, indicating that while side effects are common, the combination therapy remains a viable first-line option for advanced HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. Gao, X., Zhao, R., Ma, H., et al.[2023]

The combination of atezolizumab and bevacizumab has been shown to significantly increase overall survival in patients with advanced hepatocellular carcinoma (HCC) compared to sorafenib.

The FDA's approval of this combination therapy marks a significant advancement in the treatment of HCC, potentially changing how the disease is managed across all stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. Castet, F., Willoughby, CE., Haber, PK., et al.[2022]

Atezolizumab combined with bevacizumab is now the recommended first-line treatment for patients with unresectable or advanced hepatocellular carcinoma (HCC), supported by various national and international guidelines.

Combination therapies, including local treatments with targeted drugs like sorafenib and lenvatinib, have shown significant improvements in patient outcomes, indicating a promising direction for advanced HCC management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in targeted and immune therapies for hepatocellular carcinoma]. Nan, YM., Miao, TG.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and tolerability of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. [2022]

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

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. [2022]

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

Tiragolumab Impresses in Multiple Trials. [2021]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

A multicenter, phase Ib/II, open-label study of tivozanib with durvalumab in advanced hepatocellular carcinoma (DEDUCTIVE). [2023]

9. England pubmed.ncbi.nlm.nih.gov

Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. [2020]

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

Indirect Comparisons via Sorafenib for the Comparative Effectiveness of Two PD-1/PD-L1 Inhibitors to Treat Advanced Hepatocellular Carcinoma Patients without Prior Systemic Therapies. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab treatment for advanced hepatocellular carcinoma in the real world: a single-arm meta-analysis. [2023]

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

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. [2022]

13. China pubmed.ncbi.nlm.nih.gov

[Advances in targeted and immune therapies for hepatocellular carcinoma]. [2022]