Combination Chemotherapy for Biliary Tract Cancer

Recruiting at 5 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Georgetown University

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Ampullary adenocarcinoma, Pregnancy, CNS metastases, 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

Compensation: Varies

Number of Visits: 2

Duration: 6 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of chemotherapy drugs for people with advanced biliary tract cancer, which affects the bile ducts and gallbladder. The study targets patients whose cancer has worsened or not responded to previous treatments with gemcitabine and platinum-based drugs. It aims to determine if the combination of fluorouracil (5-FU), leucovorin, and nanoliposomal irinotecan (Nal-IRI or Onivyde) can serve as an effective second-line treatment. Individuals diagnosed with unresectable or metastatic biliary tract cancer who have undergone only one prior line of chemotherapy might be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot have had anti-cancer treatment within 3 weeks before enrolling, and you must avoid strong CYP3A4 inducers, inhibitors, or strong UGT1A1 inhibitors within 2 weeks of starting the study.

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

Research shows that a combination of three drugs—nanoliposomal irinotecan, fluorouracil, and leucovorin—has been promising in terms of safety and effectiveness. In earlier studies, this combination helped patients with biliary tract cancer and was generally well-tolerated.

Specifically, studies have found that this drug combination can extend patients' lives when used as a second option after other treatments have failed. Many patients can handle the treatment well, though some side effects might occur. Participants should discuss these with their doctors.

Overall, while every treatment carries risks, previous research supports this combination as a good option that is generally well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for biliary tract cancer because it combines nanoliposomal irinotecan with fluorouracil and leucovorin, offering a potentially more effective approach than current therapies like gemcitabine and cisplatin. The nanoliposomal formulation of irinotecan is a standout feature, as it enhances drug delivery directly to cancer cells, potentially increasing effectiveness and reducing side effects. This targeted delivery method could lead to better outcomes and a more tolerable treatment experience for patients.

What evidence suggests that this combination chemotherapy might be an effective treatment for biliary tract cancer?

Research has shown that a combination of three drugs—nanoliposomal irinotecan, fluorouracil, and leucovorin—may help treat advanced biliary tract cancer. In this trial, participants will receive this combination treatment. Studies have found that this combination can extend the time patients live without their disease worsening and improve the cancer's response to treatment. This is particularly beneficial for patients who have already tried gemcitabine-based treatments but require additional options. Early results suggest it could be a promising choice when the initial treatment is not fully effective. Overall, this combination offers hope for those with advanced biliary tract cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Benjamin Weinberg, MD

Principal Investigator

Georgetown University

Are You a Good Fit for This Trial?

This trial is for adults with advanced biliary tract cancers who've had disease progression after gemcitabine and platinum chemotherapy. They should have only received one prior chemotherapy line, be in good physical condition (ECOG 0-1), and not have central nervous system metastases or severe infections recently. Pregnant women, those with certain allergies or liver diseases, and patients on strong drug inhibitors are excluded.

Inclusion Criteria

My cancer is in the bile ducts or gallbladder and cannot be surgically removed.

My liver, kidneys, and bone marrow are functioning well.

I have had only one chemotherapy for my advanced cancer.

Exclusion Criteria

I have a blockage in my intestines.

I have no other cancers except for certain skin, prostate, cervical, or superficial bladder cancers in the last 3 years.

I have been diagnosed with cancer of the ampulla of Vater.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nanoliposomal irinotecan, leucovorin, and fluorouracil as second-line treatment for advanced biliary tract cancers

6 months

Every 2 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Fluorouracil
• Leucovorin
• Nanoliposomal Irinotecan

Trial Overview

The NAPOLI-2 study tests a combination of fluorouracil, leucovorin, and nanoliposomal irinotecan as a second-line treatment for biliary cancer following initial chemo. It aims to assess the effectiveness of this regimen in patients whose cancer has progressed despite previous treatments.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 3 Interventions

Nanoliposomal irinotecan 70 mg/ IV over 90 minutes, every 14 days. Leucovorin 400 mg/ IV over 30 minutes, every 14 days. Fluorouracil 2,400 mg/m IV over 46 hours.

Who Is Running the Clinical Trial?

Georgetown University

Lead Sponsor

Trials

355

Recruited

142,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

The LV5FU2-P chemotherapy regimen demonstrated a 34% objective response rate in 29 patients with advanced or metastatic biliary tract carcinoma, indicating its potential effectiveness in treating this challenging cancer.

The treatment was well-tolerated, with no treatment-related deaths and significant improvements in patient performance status and weight, although some patients experienced grade 3 toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Taïeb, J., Mitry, E., Boige, V., et al.[2020]

The Fufiri regimen, consisting of irinotecan, folinic acid, and 5-fluorouracil, was found to be well-tolerated in patients with advanced biliary cancer, with 27% experiencing severe drug-related side effects, primarily diarrhea and leukopenia.

Despite its tolerability, the treatment showed only modest efficacy, with a 10% objective response rate and median overall survival of 166 days for intrahepatic cholangiocarcinoma and 273 days for gallbladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas: a multicenter phase II trial. Feisthammel, J., Schoppmeyer, K., Mössner, J., et al.[2018]

In a study of 42 patients with unresectable or metastatic biliary tract or gallbladder adenocarcinoma, a combination of gemcitabine, 5-fluorouracil, and leucovorin resulted in a median survival of 9.7 months, with 57% of patients surviving 6 months or longer.

The treatment was generally manageable, with no treatment-related deaths reported, although some patients experienced severe toxicities such as nausea, fatigue, and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Alberts, SR., Al-Khatib, H., Mahoney, MR., et al.[2022]

In a study of 37 patients with advanced biliary tract cancer who did not respond to first-line gemcitabine/cisplatin treatment, the FOLFOX-4 regimen showed a median time to progression of 3.1 months, indicating moderate efficacy as a second-line treatment.

The treatment resulted in an objective response rate of 21.6% and a disease control rate of 62.2%, but also led to significant side effects, with 37.8% of patients experiencing grade 3-4 toxicities, primarily neutropenia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II FOLFOX-4 regimen as second-line treatment in advanced biliary tract cancer refractory to gemcitabine/cisplatin. He, S., Shen, J., Sun, X., et al.[2022]

The GEMFUFOL chemotherapy regimen, which includes gemcitabine, 5-fluorouracil, and leucovorin, showed promising efficacy in treating metastatic biliary tract cancer, with a median overall survival of 8.8 months and a 1-year survival rate of 58.6% among 29 patients studied over a mean follow-up of 22.1 months.

While the treatment was generally well-tolerated, it did result in significant side effects, including neutropenia in 13.7% of patients and febrile neutropenia in 6.8%, indicating the need for careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-week combination chemotherapy with gemcitabine, high-dose folinic acid and 5 fluorouracil (GEMFUFOL) as first-line treatment of metastatic biliary tract cancers. Unal, OU., Oztop, I., Unek, IT., et al.[2022]

The NIFTY trial showed that the combination of liposomal irinotecan (nal-IRI) with fluorouracil (FU) and leucovorin (LV) significantly improved progression-free survival (PFS) in patients with advanced biliary tract cancer, with a median PFS of 4.2 months compared to 1.7 months for FU/LV alone.

This updated analysis, based on 178 patients over a follow-up period of 1.3 years, indicates that nal-IRI plus FU/LV is a promising second-line treatment option for patients whose cancer progressed after initial treatment with gemcitabine and cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment With Liposomal Irinotecan Plus Fluorouracil and Leucovorin for Patients With Previously Treated Metastatic Biliary Tract Cancer: The Phase 2b NIFTY Randomized Clinical Trial. Hyung, J., Kim, I., Kim, KP., et al.[2023]

In a study of 11 patients with advanced biliary tract cancers, the combination of nanoliposomal irinotecan, leucovorin, and 5-fluorouracil (FOLFnal-IRI) showed a disease control rate of 54.5%, indicating promising antitumor potential as a second-line treatment after platinum-based chemotherapy.

The treatment was associated with a median progression-free survival of 5.1 months and an overall survival of 12.4 months, with only 3 instances of grade III toxicities, suggesting an acceptable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoliposomal irinotecan in combination with leucovorin and 5-fluorouracil in advanced biliary tract cancers. Allo, G., Can, AD., Wahba, R., et al.[2022]

In a phase 2b study involving 174 patients with advanced biliary tract cancer, the combination of liposomal irinotecan, fluorouracil, and leucovorin significantly improved progression-free survival compared to fluorouracil and leucovorin alone, with a median survival of 7.1 months versus 1.4 months.

While the treatment showed efficacy, it was associated with higher rates of serious adverse events, particularly neutropenia and fatigue, but no treatment-related deaths were reported, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Yoo, C., Kim, KP., Jeong, JH., et al.[2022]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03524508

Nal-IRI(Nanoliposomal Irinotecan) Plus 5-FU/LV in ...

The purpose of this study is to evaluate the efficacy and safety of combination of fluorouracil/folinic acid and liposomal irinotecan(Onivyde) compared with ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8764657/

Nanoliposomal irinotecan in combination with leucovorin ...

First evidence for the antitumor activity of nanoliposomal irinotecan with 5-fluorouracil and folinic acid in metastatic biliary tract cancer. Cancer Chemother ...

3.

journal-of-hepatology.eu

journal-of-hepatology.eu/article/S0168-8278(25)00169-2/fulltext

A pooled analysis of NIFTY and NALIRICC trials

Nal-IRI with 5-FU/LV improves PFS and ORR in gemcitabine-pretreated patients with BTC. •. Ethnic variations in adverse events highlight the need for ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.23.01566

A Phase II Study of the AIO Hepatobiliary-YMO Cancer ...

The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA.

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S2949819825000196

Nanoliposomal irinotecan with fluorouracil and folinic acid ...

This is the first real-world evidence of NFF. •. NFF has an appropriate efficacy and safety profile for patients with unresectable pancreatic cancer.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12049620/

Real-world outcomes of fluorouracil-based second-line ...

For survival outcomes based on tumor location, the median PFS was 2.3 months (95% CI, 1.9–2.7) for intrahepatic, 2.5 months (95% CI, 2.1–3.0) ...

7.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S2210740121001674

The efficacy and safety of 5-fluorouracil based adjuvant ...

The risk of recurrence is as high as 60-70% in the patients who underwent surgical resection in bile duct cancer. •. The 5-FU regimen is still widely used ...

8.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/15691639/

A randomised phase II trial of weekly high-dose 5 ...

This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone (HDFU) and the combination of 5FU, ...

9.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(24)00590-8/fulltext

308P Real-world outcomes of 5-FU-based second-line ...

The median progression-free survival (mPFS) and overall survival (mOS) for the entire cohort were 2.1 and 4.9 months, respectively. The mPFS was 2.1 months in ...

10.

e-crt.org

e-crt.org/journal/view.php?number=3674

A Meta-analysis Based on Individual Patient-Level Data of ...

Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should ...