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

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new combinations of treatments for biliary tract cancer that cannot be removed surgically. It examines the effectiveness of two immune therapies, atezolizumab (Tecentriq) and varlilumab, when used together, and whether adding cobimetinib (Cotellic), a drug that slows cancer cell growth, enhances their effectiveness. The trial suits individuals with biliary tract cancer who have tried one or two previous treatments and are not eligible for surgery. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from innovative therapies.

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.

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

Research has shown that using atezolizumab and varlilumab, with or without cobimetinib, is safe for patients. One study found no unexpected safety issues in people with advanced biliary tract cancer. The treatments were generally well-tolerated, and patients did not experience severe side effects that would prevent them from continuing. Both combinations have undergone previous testing, and although they did not significantly improve health outcomes, they proved safe for use. This suggests participants can expect a reasonable level of safety with these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments involving atezolizumab, varlilumab, and cobimetinib for biliary tract cancer because they offer a fresh approach compared to standard chemotherapy options. Atezolizumab is an immunotherapy that boosts the body's immune system to better attack cancer cells, while varlilumab is another immune-based treatment that targets and stimulates immune cells. Cobimetinib works differently by inhibiting specific proteins that help cancer cells grow. Unlike traditional treatments, which mainly focus on directly killing cancer cells, these therapies aim to enhance the body's natural defenses and disrupt cancer cell growth at a molecular level, providing a potentially more targeted and effective strategy.

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

This trial will evaluate the safety and effectiveness of using atezolizumab and varlilumab, with or without cobimetinib, for people with biliary tract cancer. Research has shown that using atezolizumab and varlilumab is safe, but studies found that this combination did not improve results for these patients. Atezolizumab helps the body's immune system fight cancer cells, while varlilumab strengthens the immune response to cancer. Cobimetinib stops signals that help cancer cells grow. Although this treatment is safe, its ability to improve outcomes for biliary tract cancer remains uncertain. Participants in this trial will receive either atezolizumab and varlilumab alone or in combination with cobimetinib. ^{1 2 3 4 6}

Who Is on the Research Team?

Nilofer S. Azad

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4017

A randomized phase 2 study of combination atezolizumab ... The combination of Atezolizumab and Varlilumab with or without Cobimetinib was safe but did not improve clinical outcomes in advanced stage BTC patients ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04941287

NCT04941287 | Testing A New Combination of Anti-cancer ... This helps slow or stop the spread of cancer cells. Giving atezolizumab in combination with varlilumab and cobimetinib may work better than atezolizumab and ...

3. gioncologynow.com gioncologynow.com/post/investigating-atezolizumab-varlilumab-with-or-without-cobimetinib-for-previously-treated-btc

Investigating Atezolizumab, Varlilumab With or Without ... The combination treatment of atezolizumab and varlilumab with or without cobimetinib was safe but did not improve clinical outcomes in patients ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8670844/

Multicenter randomized phase II trial of atezolizumab with ... Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the ...

5. ccanewsonline.com ccanewsonline.com/issues/2024/september-2024-vol-5-no-3/a-combination-of-atezolizumab-and-varlilumab-cdx-1127

A Combination of Atezolizumab and Varlilumab (CDX ... The study included a total of 57 patients, with 26 in the CAV group and 27 in the AV group. Among the participants in the AV group, 60.7% had intrahepatic ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.4_suppl.TPS639

ETCTN 10476: A randomized phase 2 study of ... We are conducting an open-label, randomized ph 2 trial evaluating a PD-L1 inhibitor (atezolizumab) in combination with a CD27 immune agonist (CDX-1127 [ ...