Immunotherapy Combinations for Advanced Liver Cancer

(MORPHEUS-LIVER Trial)

Recruiting in Palo Alto (17 mi)

+32 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Hoffmann-La Roche

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

Disqualifiers: Hypertension, Autoimmune disease, CNS metastases, others

No Placebo Group

Breakthrough Therapy

Trial Summary

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.

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).

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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).

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

SCRI Oncology Partners Nashville, TN

University of California San Francisco Cancer Center San Francisco, CA

UCLA Center for East Santa Monica, CA

UC Irvine Medical Center Costa Mesa, CA

More Trial Locations

Who Is Running the Clinical Trial?

Hoffmann-La Roche Lead Sponsor

NiKang Therapeutics, Inc. Industry Sponsor

Immune-Onc Therapeutics Industry Sponsor

Sanofi Industry Sponsor

Adagene Inc Industry Sponsor

Tempest Therapeutics Industry Sponsor

References

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

Safety, efficacy, and tolerability of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. [2022] Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide with an increasing incidence due to escalating rates of obesity and non-alcoholic fatty liver disease. Unfortunately, a majority of patients with HCC present with advanced disease. The immune checkpoint inhibitor atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, anti-VEGF, has become the new standard of care for patients with advanced HCC after demonstrating improved overall and progression free survival over sorafenib. In this review, we discuss the evolving role of immune checkpoint inhibitors in the treatment of HCC and their safety, efficacy, and tolerability.

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

Atezolizumab in advanced hepatocellular carcinoma: good things come to those who wait. [2022] Advanced hepatocellular carcinoma (HCC) patients present poor prognosis. However, recent years have seen the advent of several novel treatments in this setting, where the role of immune checkpoint inhibitors has been investigated. Among these, the PD-L1 inhibitor atezolizumab in combination with bevacizumab has reported unprecedented results in treatment-naive patients with unresectable disease, with the recently published IMbrave150 Phase III trial showing the superiority of the combination over sorafenib monotherapy, and after having attended more than a decade of 'stagnation', the HCC medical community has a new standard of care. Herein, we examine the development and the impact of atezolizumab in advanced HCC, summarizing the mechanism of action, pharmacokinetics and recent evidence from Phase I to III clinical trials.

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

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. [2022] The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).

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

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies. [2021] Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC.

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

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. [2022] Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need.

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

Tiragolumab Impresses in Multiple Trials. [2021] The TIGIT inhibitor tiragolumab, alone or in combination with the PD-L1 inhibitor atezolizumab, may be effective against solid cancers. In phase I and II trials, the agent achieved statistically significant results in multiple solid malignancies-most notably non-small cell lung cancer.

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

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma. [2023] The results of the IMbrave150 study have led to widespread use of the combination therapy of atezolizumab and bevacizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC). Compared to traditional cytotoxic chemotherapy agents, immune checkpoint inhibitors show a spectrum of side effects ranging from mild side effects such as skin rash to potentially severe systemic effects such as myocarditis. We present a case of transverse myelitis diagnosed during the treatment of HCC with atezolizumab and bevacizumab combination therapy.

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] Durvalumab, a PD-L1 inhibitor, is part of an immunotherapeutic drug class shown to have prolonged survival benefit in patients with advanced stage hepatocellular carcinoma (HCC). Tivozanib is a potent and selective VEGFR 1, 2 and 3 tyrosine kinase inhibitor. While these medications have both demonstrated single-agent activity in HCC and have been combined safely with other therapies, there is no data on their concurrent therapeutic effects. In the phase Ib DEDUCTIVE trial, the combination of tivozanib plus durvalumab is evaluated for safety and tolerability. Here, the design of and rationale for this trial in both treatment naive patients and those who progress on atezolizumab and bevacizumab for advanced or metastatic HCC are described. Clinical Trial Registration: NCT03970616.

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] Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.

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] Advanced hepatocellular carcinoma (HCC) represents a major public health threat. Several emerging combination therapies have shown promising results for the first-line treatment of advanced HCC. The present study compared the efficacy of atezolizumab plus bevacizumab (AB) with lenvatinib plus pembrolizumab (LP), which were two of the leading combination therapies.

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] Atezolizumab plus bevacizumab was approved in 2020 as a first-line treatment for advanced hepatocellular carcinoma (HCC). The purpose of this study was to assess the curative effect and tolerability of the combination treatment in advanced HCC.

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

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma. [2022] The combination of atezolizumab and bevacizumab increases overall survival compared with sorafenib in advanced hepatocellular carcinoma (HCC). Its approval by the FDA has launched a new era of combination therapies in advanced and earlier settings that are likely to reshape the management of HCC across all disease stages.See related article by Casak et al., p. 1836.

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

[Advances in targeted and immune therapies for hepatocellular carcinoma]. [2022] Targeted and immunotherapy drugs for hepatocellular carcinoma (HCC) have been rapidly developed. Atezolizumab in combination with bevacizumab has been recommended as the first-line standard of care for unresectable or advanced HCC in several national and international guidelines. The combination therapies with sindilizumab and bevacizumab biosimilar, apatinib and carrilizumab, dulvalizumab and tremelimumab are also recommended as first-line standard regimens for advanced HCC in the guideline of Chinese Society of Clinical Oncology. Local therapy combined with targeted drugs (such as sorafenib and lenvatinib) or immune checkpoint inhibitors can significantly improve outcomes. Therefore, some progress has also been made in the study of single-agent or combination regimens as perioperative neoadjuvant therapy.