Atezolizumab + Varlilumab (+/- Cobimetinib) for Biliary Tract Cancer

Recruiting at 32 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, CYP3A inhibitors

Disqualifiers: Transplant, CNS metastases, severe infections, others

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

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: 58

Duration: Up to 2 years

57 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that certain medications, especially those that interact with cobimetinib, may need to be adjusted. It's important to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the drug combination Atezolizumab and Cobimetinib for biliary tract cancer?

A study showed that combining Atezolizumab with Cobimetinib helped patients with biliary tract cancer live longer without the disease getting worse compared to using Atezolizumab alone, although the overall response was still low. ^{1 2 3 4 5}

What safety data exists for Atezolizumab and Cobimetinib in humans?

In a study with patients having biliary tract cancer, the combination of Atezolizumab and Cobimetinib was linked to more skin rashes, stomach issues, increased muscle enzyme levels, and low platelet counts compared to Atezolizumab alone. ^{1 2 3 4 5}

How is the drug combination of Atezolizumab, Varlilumab, and Cobimetinib unique for treating biliary tract cancer?

This drug combination is unique because it combines Atezolizumab, an immunotherapy drug that blocks PD-L1 to help the immune system attack cancer cells, with Cobimetinib, which is thought to enhance the immune response by inhibiting MEK, and Varlilumab, which may further stimulate the immune system. This approach aims to overcome the immune-resistant nature of biliary tract cancers, which typically respond poorly to single-agent immunotherapies. ^{1 2 3 4 6}

What is the purpose of this trial?

This phase II trial investigates the effect of combining two immune therapies, atezolizumab and CDX-1127 (varlilumab), with or without cobimetinib, in treating patients with biliary tract cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Varlilumab is an immune agonist antibody that may further strengthen the immune system's attack on the cancer. Cobimetinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab in combination with varlilumab and cobimetinib may work better than atezolizumab and varlilumab alone in treating patients with unresectable biliary tract cancer.

Research Team

Nilofer S. Azad

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

This trial is for adults with advanced biliary tract cancer that can't be surgically removed, who've had at least one but no more than two prior treatments. They must have a life expectancy over 3 months, good physical function, acceptable blood counts and organ function, agree to use contraception, and be willing to undergo biopsies. Those with certain viral infections must have undetectable viral loads.

Inclusion Criteria

Agreement to use adequate contraception

My biliary tract cancer has been treated with 1 or 2 therapies after spreading.

No evidence of retinal pathology on ophthalmologic examination

Exclusion Criteria

Prior allogeneic bone marrow transplantation within the past 5 years or prior solid organ transplantation at any point

I have a history of heart problems.

Treatment with certain investigational agents or immunostimulatory agents within specified timeframes

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Visits every 28 days, with imaging every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 3 months until death, withdrawal of consent, or study closure

Follow-up at 30 days post-treatment, then every 3 months

Treatment Details

Interventions

• Atezolizumab
• Cobimetinib
• Varlilumab

Trial Overview The study tests combining two immune therapies (Atezolizumab and Varlilumab) with or without Cobimetinib in patients whose biliary tract cancer cannot be operated on. It explores whether this combination helps the immune system fight cancer better than just Atezolizumab and Varlilumab alone.

Participant Groups

Group I: Arm B (atezolizumab, varlilumab) Experimental Treatment 6 Interventions

Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 of each cycle and varlilumab IV over 90 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, every 8 weeks while on treatment, and at end of treatment or progression. Patients also undergo a tumor biopsy at baseline and on day 21 of cycle 1. Patients also undergo blood sample collection on study.

Group II: Arm A (cobimetinib, atezolizumab, varlilumab) Experimental Treatment 7 Interventions

Patients receive cobimetinib PO QD on days 1-21 of each cycle, atezolizumab IV over 30-60 minutes on days 1 and 15 of each cycle, and varlilumab IV over 90 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, every 8 weeks while on treatment, and at end of treatment or progression. Patients also undergo a tumor biopsy at baseline and on day 21 of cycle 1. Patients also undergo blood sample collection on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II study involving 77 patients with unresectable biliary tract cancers, the combination of atezolizumab (anti-PD-L1) and cobimetinib (MEK inhibitor) significantly improved progression-free survival (PFS) to a median of 3.65 months compared to 1.87 months for atezolizumab alone.

Despite the improved PFS, the overall response rates were low in both treatment groups, indicating that biliary tract cancers may be resistant to immune therapies, and combination therapy was associated with increased side effects such as rash and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. Yarchoan, M., Cope, L., Ruggieri, AN., et al.[2023]

In a phase II study involving 127 patients with advanced biliary tract cancer, the combination of varlitinib and capecitabine showed a modest objective response rate of 9.4%, compared to 4.8% for capecitabine alone, but did not significantly improve progression-free survival (PFS) or overall survival.

While the overall efficacy was similar to capecitabine alone, a subgroup analysis indicated potential PFS benefits for female patients and those with gallbladder cancer, suggesting that varlitinib may be more effective in these specific groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Varlitinib plus capecitabine in second-line advanced biliary tract cancer: a randomized, phase II study (TreeTopp). Javle, MM., Oh, DY., Ikeda, M., et al.[2022]

In a study of 30 patients with previously treated HER2-positive metastatic biliary tract cancer, the combination of tucatinib and trastuzumab showed a confirmed objective response rate of 46.7%, indicating significant antitumor activity.

The treatment was generally well tolerated, with common side effects including fever and diarrhea, but no deaths were attributed to treatment-related adverse events, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. Nakamura, Y., Mizuno, N., Sunakawa, Y., et al.[2023]

In a study of 210 patients with advanced biliary tract carcinoma, PD-1 monoclonal antibody (PD-1-mAb) combination therapy significantly improved median progression-free survival (mPFS) and median overall survival (mOS) compared to standard chemotherapy in both first-line and second-line treatments.

Specifically, the first-line PD-1-mAb combination group had a mPFS of 7.3 months and mOS of 15.6 months, while the second-line group had a mPFS of 6.1 months and mOS of 11.7 months, indicating that PD-1-mAb combinations are promising treatment options for this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis. Wang, F., Wang, FH., Sun, K., et al.[2022]

References

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

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers. [2023]

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

Varlitinib plus capecitabine in second-line advanced biliary tract cancer: a randomized, phase II study (TreeTopp). [2022]

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

Atezolizumab: an investigational agent for the treatment of biliary tract cancer. [2022]

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

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Targeting PD-1/PD-L1 in biliary tract cancer: role and available data. [2023]

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

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis. [2022]