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?

Background: Biliary tract carcinoma (BTC) is cancer of the slender tubes that carry fluids in the liver. People with advanced BTC have few treatment options, and their survival rates are very low. Objective: To test a study drug (CDX-1140) combined 3 other drugs (capecitabine, oxaliplatin, Keytruda) in people with BTC. Eligibility: Adults aged 18 years or older with BTC that progressed after treatment and is not eligible for surgery or liver transplant. Design: Participants will be screened. They will have a physical exam. They will have blood tests and tests of their heart function. They will have imaging scans. They may need to have a biopsy: A small sample of tissue will be taken from their tumor using a small needle. Three of the drugs are given through a tube attached to a needle inserted into a vein in the arm (intravenous). The fourth drug is a pill taken by mouth with water. Participants will be treated in 21-day cycles. They will receive intravenous treatments on day 1 and day 8 of the first 6 cycles. After that, they will receive intravenous treatments only on day 1 of each cycle. Participants will take the pill twice a day only for the first 2 weeks of each cycle. They will stop taking this drug after 6 cycles. Imaging scans will be repeated every 9 weeks. Participants may continue receiving the study treatment for up to 2 years. Follow-up visits, including imaging scans, will continue for 3 more years. These images may be taken at other locations and sent to the researchers.

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 the combination of CDX-1140, CAPOX, and Keytruda safe for humans?

The combination of capecitabine and oxaliplatin (CAPOX) has been shown to be generally well-tolerated in patients with advanced biliary system cancers, with the most common serious side effect being peripheral sensory neuropathy (nerve damage causing tingling or numbness). ^{1 2 3 4 5}

What makes the CDX-1140 + CAPOX + Keytruda treatment unique for bile duct cancer?

This treatment is unique because it combines CDX-1140, an experimental drug that stimulates the immune system, with CAPOX (capecitabine and oxaliplatin), a chemotherapy regimen, and Keytruda (pembrolizumab), an immunotherapy drug. This combination aims to enhance the body's immune response against cancer cells, which is different from standard chemotherapy alone. ^{2 3 6 7 8}

What data supports the effectiveness of the drug combination CDX-1140 + CAPOX + Keytruda for bile duct cancer?

Research shows that the combination of pembrolizumab (Keytruda) with capecitabine and oxaliplatin (CAPOX) has been studied in patients with advanced biliary tract cancer, showing some clinical efficacy. Additionally, CAPOX alone has been found to be an active treatment option for certain types of advanced biliary cancers, suggesting potential benefits when combined with other therapies like CDX-1140. ^{3 9 10 11 12}

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 haven't had cancer treatment in the last 4 weeks.

I have previously been treated with anti-CD40 therapy.

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 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]

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 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]

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]

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]

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 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 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. England 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. [2022]

2. England 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. [2022]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Third-Line Palliative Systemic Therapy for Advanced Biliary Tract Cancer: Multicentre Review of Patterns of Care and Outcomes. [2023]

5. 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]

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

Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. [2022]

7. China pubmed.ncbi.nlm.nih.gov

[Preliminary study of XELOX regimen as the first-line chemotherapy in advanced or recurrent gastric cancer]. [2020]

8. United States 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. [2022]

9. China pubmed.ncbi.nlm.nih.gov

[Oxaliplatin plus capecitabine as a second line chemotherapy for patients with advanced gastric cancer]. [2018]

10. Japan pubmed.ncbi.nlm.nih.gov

[CapeOX Therapy as a Salvage Treatment for Advanced Gastric Cancer Refractory to S-1, Cisplatin, Irinotecan, and Taxanes]. [2019]

11. England 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. [2020]

12. Greece pubmed.ncbi.nlm.nih.gov

XELOX vs. FOLFOX4 as second line chemotherapy in advanced pancreatic cancer. [2022]