CDX-1140 + CAPOX + Keytruda for Bile Duct Cancer

Overseen By Tim F Greten, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: HIV, Pneumonitis, Autoimmune diseases, others

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

Compensation: Varies

Number of Visits: 11

Duration: Up to 2 years

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs for bile duct cancer, which affects the tubes carrying fluids in the liver. The researchers aim to determine if adding the study drug, CDX-1140 (an experimental treatment), to three existing treatments (capecitabine, oxaliplatin, and Keytruda) benefits those whose cancer has worsened after other treatments. It is open to individuals with bile duct cancer that cannot be treated with surgery or a liver transplant. Participants will receive some medications via IV and one as a pill, with treatments lasting up to two years and regular check-ups for three more years.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or other immunosuppressive medications, you may not be eligible to participate.

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

Previous studies have generally found CDX-1140 to be well-tolerated, especially when combined with pembrolizumab (Keytruda). This combination has shown early signs of effectiveness in treating certain solid tumors. Research on Keytruda has found serious side effects in about 28% of patients, including pneumonia and colitis, which is inflammation of the colon. However, Keytruda may also provide lasting immune responses for some patients with biliary tract cancer.

Capecitabine, when used alone, has been safe even for patients with jaundice, a yellowing of the skin due to liver issues. It remains a common treatment for biliary tract cancer. Additionally, oxaliplatin, another chemotherapy drug, has demonstrated a good rate of disease control, helping to stop the cancer from worsening for a while in many patients.

This trial is in its early stages, so researchers are still studying the safety of the drug combination and determining the best doses. While these early stages focus on safety, later stages will provide more detailed information on the treatment's effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining CDX-1140 with CAPOX (capecitabine and oxaliplatin) and Keytruda for treating bile duct cancer because it introduces a novel approach to tackling this tough condition. CDX-1140 is a new type of immunotherapy that activates the CD40 pathway, which can boost the body's immune response against cancer cells. Unlike current standard treatments that largely focus on chemotherapy, CDX-1140 aims to enhance the effectiveness of the immune system, offering a potentially more targeted attack on the cancer. This combination could lead to improved outcomes by not only slowing the cancer's progression but also by potentially improving the body's natural ability to fight the disease.

What evidence suggests that this trial's treatments could be effective for bile duct cancer?

This trial will investigate the combination of CDX-1140, pembrolizumab (Keytruda), capecitabine, and oxaliplatin for bile duct cancer. Research has shown that combining CDX-1140 and pembrolizumab may be promising for patients with hard-to-treat solid tumors, showing early positive results. Pembrolizumab, when used with chemotherapy, has helped patients with biliary tract cancer live longer and respond well to treatment. The combination of capecitabine and oxaliplatin is effective as a second treatment option for advanced biliary tract cancers, with studies indicating they help manage the disease. Oxaliplatin alone has also controlled advanced cases effectively. Overall, these treatments together may offer a new option for those with advanced biliary tract cancer, addressing the need for more effective therapies. ^{2 3 4 5 6}

Who Is on the Research Team?

Tim F Greten, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with advanced Biliary Tract Carcinoma (BTC) that's worsened after treatment and can't be removed by surgery or improved with a liver transplant. They must have acceptable organ function, no recent major surgeries, not be pregnant, and agree to use contraception. People who've had certain vaccines recently, those with HIV or active CNS metastases, or a history of severe allergies to similar drugs are excluded.

Inclusion Criteria

My organs and bone marrow are functioning well.

My largest tumor or metastasis is 8 cm or smaller.

I am breastfeeding but willing to stop during the study.

Exclusion Criteria

I am on long-term steroids or other drugs that weaken my immune system.

I have previously been treated with anti-CD40 therapy.

I have not received any live vaccines in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive CDX-1140, capecitabine, oxaliplatin, and Keytruda in 21-day cycles. Intravenous treatments are given on day 1 and day 8 for the first 6 cycles, and only on day 1 thereafter. The pill is taken twice a day for the first 2 weeks of each cycle, stopping after 6 cycles.

Up to 2 years

Intravenous treatments on day 1 and day 8 for the first 6 cycles, then only on day 1

Follow-up

Participants are monitored for safety and effectiveness after treatment, with imaging scans repeated every 9 weeks and follow-up visits continuing for 3 more years.

3 years

Imaging scans every 9 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• CDX-1140
• Keytruda
• Oxaliplatin

Trial Overview The trial is testing CDX-1140 in combination with Capecitabine (a pill), Oxaliplatin (intravenous), and Keytruda (intravenous) for BTC treatment. Participants will undergo cycles of these treatments: intravenous on days 1 and 8 for the first six cycles then day 1 only afterward; pills taken twice daily for two weeks each cycle but stopped after six cycles.

How Is the Trial Designed?

Group I: Phase II Experimental Treatment 4 Interventions

Keytruda, oxaliplatin, capecitabine and estimated safe dose of CDX-1140

Group II: Phase I Experimental Treatment 4 Interventions

Keytruda, oxaliplatin, capecitabine and escalating doses of CDX-1140

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

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

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

The combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) was well tolerated in a phase II study involving 11 patients with advanced biliary tract carcinoma, showing a disease control rate of 81.8% and a median progression-free survival of 4.1 months.

Out of the participants, 27.3% achieved a partial response, indicating that this treatment regimen may be effective for patients with refractory advanced biliary tract carcinoma, especially considering the exploratory analysis of immune responses and tumor evolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Pembrolizumab in Combination with Capecitabine and Oxaliplatin with Molecular Profiling in Patients with Advanced Biliary Tract Carcinoma. Monge, C., Pehrsson, EC., Xie, C., et al.[2022]

In a study of 94 patients aged 70 and older with advanced colorectal cancer, both CAPOX and CAPIRI treatments showed similar overall response rates (38% for CAPOX and 36% for CAPIRI), indicating comparable efficacy as first-line treatments.

CAPOX was better tolerated than CAPIRI, with fewer severe side effects such as diarrhea and neutropenia, suggesting it may be a safer option for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine in combination with oxaliplatin or irinotecan in elderly patients with advanced colorectal cancer: results of a randomized phase II study. Rosati, G., Cordio, S., Bordonaro, R., et al.[2020]

In a study of 24 patients with advanced gastric cancer, the combination of oxaliplatin and capecitabine showed an overall response rate of 29.2%, indicating it can be an effective second-line chemotherapy option.

The treatment was generally well tolerated, with major side effects including bone marrow suppression and nausea/vomiting, and it provided a median time to tumor progression of 5 months and a median duration of remission of 8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oxaliplatin plus capecitabine as a second line chemotherapy for patients with advanced gastric cancer]. Qian, J., Qin, SK., Mei, JF., et al.[2018]

In a study of 12 patients with advanced gastric cancer who had already been treated with multiple therapies, the combination of capecitabine and oxaliplatin (CapeOX) showed a modest overall response rate of 16.7% and a disease control rate of 75% at 6 weeks.

CapeOX therapy resulted in a progression-free survival of 3.1 months and an overall survival of 8.3 months, with manageable side effects, including grade 3 neutropenia in 50% of patients, suggesting it may be a viable salvage treatment for patients with good performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CapeOX Therapy as a Salvage Treatment for Advanced Gastric Cancer Refractory to S-1, Cisplatin, Irinotecan, and Taxanes]. Okagawa, Y., Sagawa, T., Sakurada, A., et al.[2019]

In a study of 65 patients with advanced biliary system adenocarcinomas, the combination therapy of capecitabine and oxaliplatin (CAPOX) showed a 27% response rate in patients with gallbladder carcinoma (GBC) and extrahepatic cholangiocarcinoma (ECC), indicating its efficacy for these types of cancer.

The CAPOX regimen was well tolerated overall, with the most common severe side effect being peripheral sensory neuropathy in 11 patients, suggesting it is a viable treatment option for advanced GBC and ECC, but less effective for intrahepatic cholangiocarcinoma (ICC), which had no objective responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial. Nehls, O., Oettle, H., Hartmann, JT., et al.[2022]

Capecitabine, an oral medication, showed at least equivalent efficacy to intravenous 5-FU plus leucovorin in treating metastatic colorectal cancer, with an overall response rate of 18.9% compared to 15.0% for 5-FU/LV among 602 patients.

Capecitabine had a more favorable safety profile, resulting in significantly lower rates of stomatitis and neutropenia, while being associated with a higher incidence of hand-foot syndrome, making it a convenient and effective alternative to traditional IV treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Van Cutsem, E., Twelves, C., Cassidy, J., et al.[2022]

The XELOX regimen, combining oxaliplatin and capecitabine, demonstrated a 41.5% overall response rate in 41 patients with advanced or recurrent gastric cancer, indicating its efficacy in this challenging condition.

The treatment was associated with manageable toxicity, with only a few patients experiencing severe side effects, such as grade 3-4 neural toxicity and hematological issues, suggesting it is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preliminary study of XELOX regimen as the first-line chemotherapy in advanced or recurrent gastric cancer]. Min, N., He, BF., Zhang, LS., et al.[2020]

In a study of 42 patients with metastatic or locally advanced pancreatic cancer, capecitabine demonstrated a clinical benefit response in 24% of patients, improving pain intensity and overall performance status.

Capecitabine was generally well tolerated, with a 9.5% objective response rate, suggesting it may be a viable treatment option for further evaluation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. Cartwright, TH., Cohn, A., Varkey, JA., 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 study of 97 patients with advanced biliary cancer receiving third-line systemic therapy, the median progression-free survival was 3.1 months and median overall survival was 6.4 months, indicating limited efficacy of current 3L treatment options.

Patients with therapy-targeted molecular aberrations had significantly better overall survival (12.5 months) compared to those without such aberrations (5.9 months), highlighting the potential for personalized treatment approaches in advanced biliary cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Third-Line Palliative Systemic Therapy for Advanced Biliary Tract Cancer: Multicentre Review of Patterns of Care and Outcomes. Gray, S., Letissier, O., d'Abrigeon, C., et al.[2023]

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 study of 85 patients with advanced pancreatic cancer who had previously failed gemcitabine-based chemotherapy, oxaliplatin combined with capecitabine (XELOX) showed a disease control rate of 59%, while the combination with folinic acid and 5-FU (FOLFOX4) had a rate of 43%.

Both treatment regimens demonstrated moderate clinical activity with acceptable toxicity, with median overall survival being 21 weeks for XELOX and 25 weeks for FOLFOX4, indicating that both are viable second-line options for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

XELOX vs. FOLFOX4 as second line chemotherapy in advanced pancreatic cancer. Berk, V., Ozdemir, N., Ozkan, M., et al.[2022]

Citations

1. onclive.com onclive.com/view/cdx-1140-plus-pembrolizumab-elicits-responses-in-pd-1-pd-l1-resistant-solid-tumors

CDX-1140 Plus Pembrolizumab Elicits Responses in PD-1/ ... The utilization of the anti-CD40 agonist, CDX-1140, in combination with pembrolizumab was generally well tolerated and demonstrated preliminary efficacy.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11028348/

Development of CDX-1140, an agonist CD40 antibody for ... CDX-1140 does not promote cytokine production in whole blood assays and has good pharmacodynamic and safety profiles in cynomolgus macaques.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03329950

NCT03329950 | A Study of CDX-1140 (CD40) as ... This study will determine the MTD of CDX-1140 while also evaluating the safety, tolerability and efficacy of CDX-1140 alone (Part 1) or in combination with CDX- ...

4. withpower.com withpower.com/trial/phase-2-bile-duct-neoplasms-4-2023-229a9

CDX-1140 + CAPOX + Keytruda for Bile Duct Cancer The combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) was well tolerated in a phase II study involving 11 patients with advanced biliary ...

5. youtube.com youtube.com/watch?v=hjv-8qpdpD0

CCF Webinar: Exploring New Options for Advanced Biliary ... Exploring a New Treatment Option for Advanced Biliary Tract Cancer Featuring CDX-1140, CAPOX, and Keytruda® This webinar will cover key ...

6. ccanewsonline.com ccanewsonline.com/issues/2023/june-2023-vol-4-no-2/3013:cdx-1140-plus-capecitabine-oxaliplatin-and-pembrolizumab-in-advanced-btc

CDX-1140 Plus Capecitabine, Oxaliplatin, and ... A new phase 2 study that aims to investigate the CD40 agonist CDX-1140 in combination with capecitabine, oxaliplatin, and pembrolizumab in advanced biliary ...