Triple-Drug Combo for Liver Cancer

(RELATIVITY-106 Trial)

Recruiting at 124 trial locations

Overseen By BMS Study Connect Contact Center www.BMSStudyConnect.com

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bristol-Myers Squibb

Disqualifiers: Fibrolamellar HCC, 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

Duration: 12 weeks

162 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and effectiveness of triplet therapy of nivolumab, relatlimab and bevacizumab versus nivolumab and bevacizumab in participants with untreated advanced/metastatic hepatocellular carcinoma (HCC).

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

The protocol does not specify if you need to stop taking your current medications.

Will I have to stop taking my current medications?

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

What data supports the idea that Triple-Drug Combo for Liver Cancer is an effective treatment?

The available research shows that combining drugs like atezolizumab and bevacizumab can significantly improve survival rates and reduce cancer recurrence in liver cancer patients. For example, the IMbrave 050 trial demonstrated that this combination was more effective than just monitoring patients after surgery. Although the Triple-Drug Combo specifically isn't directly compared in the studies, similar combinations have shown promise in improving outcomes for liver cancer patients. ^{1 2 3 4 5}

What data supports the effectiveness of the triple-drug combo for liver cancer?

Research shows that combining immune checkpoint inhibitors, like nivolumab, with other treatments has shown promise in improving outcomes for liver cancer. Additionally, bevacizumab, when combined with other drugs, has been effective in improving survival rates in liver cancer patients. ^{1 2 3 4 5}

What safety data is available for the triple-drug combo treatment for liver cancer?

The safety data for the triple-drug combo treatment involving Bevacizumab (Avastin), Nivolumab (Opdivo), and Relatlimab (Opdualag, BMS-986016, relatlimab-rmbw) is not directly addressed in the provided research. However, similar combinations of immune checkpoint inhibitors and anti-VEGF agents have been studied. For instance, the combination of atezolizumab (an anti-PD-L1) and bevacizumab (an anti-VEGF) has been evaluated for safety in unresectable hepatocellular carcinoma, showing enhanced anticancer immunity. Additionally, PD-1/PD-L1 inhibitors have been assessed for safety in advanced hepatocellular carcinoma, sometimes in combination with anti-CTLA-4 or anti-VEGF agents. These studies suggest that while such combinations can enhance antitumor activity, they may also increase the incidence of adverse events. ^{6 7 8 9 10}

What safety data exists for the triple-drug combo treatment for liver cancer?

Bevacizumab (also known as Avastin) has been studied in combination with other drugs for liver cancer, showing that it can be generally safe in humans. Nivolumab (Opdivo) and Relatlimab (Opdualag) have also been evaluated for safety in various conditions, indicating they are generally safe, though side effects like reduced appetite and diarrhea have been reported. ^{6 7 8 9 10}

Is the drug combination of Bevacizumab, Nivolumab, and Relatlimab a promising treatment for liver cancer?

The combination of Bevacizumab, Nivolumab, and Relatlimab is promising because similar drug combinations have shown success in treating liver cancer. For example, Bevacizumab combined with another drug, Atezolizumab, is already a recommended treatment for liver cancer. This suggests that combining Bevacizumab with other drugs like Nivolumab and Relatlimab could also be effective. ^{1 4 11 12 13}

How is the triple-drug combo for liver cancer different from other treatments?

The triple-drug combo for liver cancer is unique because it combines Bevacizumab, Nivolumab, and Relatlimab, which are drugs that target different aspects of the cancer and immune system. This combination aims to enhance the body's immune response against cancer cells, potentially offering a new approach for patients who have not responded well to other treatments. ^{1 4 11 12 13}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with advanced liver cancer (HCC) who haven't had systemic therapy for it. They should have a good level of liver function (Child-Pugh A) and be able to carry out daily activities with little or no help (ECOG 0-1). People can't join if they've had organ transplants, certain types of HCC, untreated brain metastases, or significant fluid in the abdomen.

Inclusion Criteria

My liver function is slightly impaired.

I have not had systemic therapy for advanced liver cancer, but prior immunotherapy is okay if my cancer returned 6 months after treatment.

I am fully active or can carry out light work.

Exclusion Criteria

Other protocol-defined inclusion/exclusion criteria apply

I have had a previous organ or stem cell transplant.

My liver cancer is a specific type (fibrolamellar, sarcomatoid, or mixed with bile duct cancer).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive triplet therapy of nivolumab, relatlimab, and bevacizumab or placebo with nivolumab and bevacizumab

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Bevacizumab
• Nivolumab
• Relatlimab

Trial Overview The study tests combining Nivolumab and Relatlimab with Bevacizumab against just Nivolumab and Bevacizumab in treating advanced liver cancer. It aims to see which combination is safer and more effective for patients who haven't received prior treatment for their condition.

Participant Groups

Group I: Arm B: Placebo + Nivolumab + Bevacizumab Experimental Treatment 3 Interventions

Group II: Arm A: Relatlimab + Nivolumab + Bevacizumab Experimental Treatment 3 Interventions

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Atezolizumab combined with Bevacizumab has been approved for treating hepatocellular carcinoma (HCC) in patients who have not responded to other treatments, highlighting its potential efficacy in a challenging clinical setting.

The case study of a 37-year-old male with recurrent HCC showed that despite receiving multiple therapies, including PD-1 blockade and targeted therapy, the patient ultimately succumbed to severe immune rejection after liver transplantation, indicating the complexities and risks associated with advanced HCC treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen. Yin, J., Wen, M., Cheng, J., et al.[2022]

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and while surgery and local therapies can be curative, many patients are diagnosed at advanced stages or experience recurrence.

Recent research highlights the potential of combining two immune checkpoint inhibitors (ICIs), specifically nivolumab with ipilimumab and durvalumab with tremelimumab, as a promising immunotherapy strategy for HCC, building on their success in treating other solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand? Carloni, R., Rizzo, A., Ricci, AD., et al.[2022]

Atezolizumab (a PD-L1 inhibitor) combined with bevacizumab (a VEGF inhibitor) has shown significant improvements in survival and response rates for patients with unresectable hepatocellular carcinoma (HCC).

The IMbrave 050 study is designed to evaluate whether this combination therapy can reduce recurrence rates in high-risk HCC patients after curative treatment, with the primary focus on recurrence-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Hack, SP., Spahn, J., Chen, M., et al.[2021]

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 1/2 study involving 148 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, the combination of nivolumab and ipilimumab showed a promising objective response rate of 32% in one treatment arm, indicating potential efficacy for this patient population.

The treatment regimen was generally manageable in terms of safety, although 94% of patients in one arm experienced treatment-related adverse events, highlighting the need for careful monitoring; notably, this combination therapy received accelerated approval in the US based on these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. Yau, T., Kang, YK., Kim, TY., 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]

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 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]

In a real-world study of 145 patients with advanced biliary tract cancer, the combination of durvalumab with gemcitabine and cisplatin achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 12.9 months, confirming the efficacy seen in the TOPAZ-1 trial.

The treatment was associated with a high rate of adverse events (94.5%), with 35.2% experiencing severe (grades 3-4) adverse events, but only 2.1% had severe immune-mediated adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data. Rimini, M., Fornaro, L., Lonardi, S., et al.[2023]

In a review of 13 trials involving 2,386 patients with unresectable hepatocellular carcinoma (HCC), PD-L1/PD-1 inhibitors demonstrated a moderate overall response rate (ORR) of 21% and a disease control rate (DCR) of 59%, indicating their effectiveness in treating advanced HCC.

Combining PD-L1/PD-1 inhibitors with anti-VEGF agents significantly improved treatment outcomes, achieving an ORR of 26% and a progression-free survival (PFS) of 6.2 months, compared to lower results with PD-L1/PD-1 monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of PD-1/PD-L1 inhibitors in patients with advanced hepatocellular carcinoma: a systematic review and meta-analysis. Wen, W., Zhang, Y., Zhang, H., et al.[2023]

In the phase 3 HIMALAYA study, the STRIDE regimen (tremelimumab plus durvalumab) significantly improved survival rates for patients with unresectable hepatocellular carcinoma (HCC) compared to sorafenib, the standard treatment.

Patients receiving STRIDE or durvalumab experienced a lower risk of worsening quality of life and manageable side effects, indicating that these immunotherapy options may offer a better overall treatment experience than sorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer). Abou-Alfa, GK., Lau, G., Kudo, M., et al.[2023]

In a study of 191 patients with unresectable hepatocellular carcinoma (HCC), the combination therapy of atezolizumab and bevacizumab showed similar overall survival and progression-free survival rates in older patients (≥65 years) compared to younger patients (<65 years), indicating its efficacy across age groups.

The safety profile of the combination therapy was comparable between older and younger patients, with similar rates of treatment-related adverse events, including severe adverse events, suggesting that older patients can tolerate this treatment as well as younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. Vithayathil, M., D'Alessio, A., Fulgenzi, CAM., et al.[2023]

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. Switzerland pubmed.ncbi.nlm.nih.gov

A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen. [2022]

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

Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand? [2022]

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

IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. [2021]

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

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

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

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. [2022]

6. 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]

7. 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]

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

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

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

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

Clinical outcomes of PD-1/PD-L1 inhibitors in patients with advanced hepatocellular carcinoma: a systematic review and meta-analysis. [2023]

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

Plain language summary of the HIMALAYA study: tremelimumab and durvalumab for unresectable hepatocellular carcinoma (liver cancer). [2023]

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

Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma. [2023]

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

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