Combination Chemotherapy + Immunotherapy for Biliary Tract Cancer

Overseen By Joann Santmyer, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Chemotherapy, Radiotherapy, Corticosteroids, others

Disqualifiers: HIV/AIDS, Autoimmune disease, 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: Unknown

Duration: 8-12 weeks

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of chemotherapy and immunotherapy to determine its safety and effectiveness for treating biliary tract cancer (BTC), which affects the bile ducts. Researchers are examining whether the combination of gemcitabine, cisplatin, and pembrolizumab (an immunotherapy drug) can shrink the cancer. Individuals recently diagnosed with BTC that can be surgically removed might be suitable candidates. The study aims to discover if these treatments can work together to improve outcomes for BTC patients. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to the development of potentially effective therapies.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on systemic chemotherapy or investigational agents for biliary tract cancer, you would not be eligible to participate.

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

Research shows that using gemcitabine, cisplatin, and pembrolizumab together is generally safe. Studies have found that patients with biliary tract cancer tolerate this combination well.

In a previous study, adding pembrolizumab to gemcitabine and cisplatin did not lead to more severe side effects. Common side effects included tiredness and nausea, typical for chemotherapy. Serious side effects were not significantly higher than with chemotherapy alone.

Gemcitabine and cisplatin have long been used in cancer treatment, and pembrolizumab is already approved for other cancers, indicating its safety is well understood. This suggests the combination should be safe for most patients. However, anyone considering joining a trial should discuss potential risks with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for biliary tract cancer?

Researchers are excited about this combination treatment for biliary tract cancer because it uniquely pairs standard chemotherapy drugs, cisplatin and gemcitabine, with pembrolizumab, an immunotherapy drug. Pembrolizumab works by unleashing the immune system to attack cancer cells, a mechanism not typically utilized in standard treatments for this type of cancer. This approach has the potential to enhance the effectiveness of chemotherapy by also engaging the body's natural defenses, which could lead to better patient outcomes.

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

Research has shown that adding pembrolizumab to the usual chemotherapy drugs, gemcitabine and cisplatin, can benefit patients with advanced biliary tract cancer. In this trial, participants will receive a combination of gemcitabine, cisplatin, and pembrolizumab. Studies have found that this combination improves overall survival compared to using only gemcitabine and cisplatin. Pembrolizumab enhances the immune system's ability to fight cancer. Early results suggest this combination may outperform chemotherapy alone, offering hope for better treatment outcomes for patients with this type of cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Marina Baretti, M.D.

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed, biopsy-proven biliary tract cancer that can potentially be removed by surgery. Participants must have good performance status, adequate organ function, and controlled hepatitis if present. They should not have HIV/AIDS or active autoimmune diseases and must agree to use birth control.

Inclusion Criteria

My liver is working well, according to recent tests.

I am fully active or able to carry out light work.

Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

I do not have any severe illnesses that could interfere with the study.

Evidence of clinical ascites

I have had a transplant of tissue, organ, or bone marrow from another person.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive peri-operative gemcitabine, cisplatin, and pembrolizumab

8-12 weeks

Surgery

Participants proceed to surgery without an extended treatment-related delay

Up to 144 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Gemcitabine
• Pembrolizumab

Trial Overview The study tests the safety and effectiveness of a combination treatment using gemcitabine, cisplatin, and pembrolizumab before and after potential surgery in patients with biliary tract cancers. It aims to see if this regimen leads to significant tumor shrinkage.

How Is the Trial Designed?

Group I: Gemcitabine, Cisplatin and Pembrolizumab Experimental Treatment 3 Interventions

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a Phase 2 trial involving 51 patients with advanced biliary tract cancer, adding the MEK inhibitor selumetinib to standard chemotherapy (Cisplatin and gemcitabine) did not improve tumor size reduction or survival outcomes compared to chemotherapy alone.

Patients receiving selumetinib experienced higher rates of severe toxicities and required more dose reductions of chemotherapy, indicating that the combination may not be safe or effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised, Phase II study of selumetinib, an oral inhibitor of MEK, in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer. Doherty, MK., Tam, VC., McNamara, MG., 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 phase 2 trial involving 75 patients with advanced biliary tract cancer, the combination of nivolumab with gemcitabine and cisplatin (Arm A) resulted in a significantly higher 6-month progression-free survival (PFS) rate of 59.4% compared to 21.2% in the group receiving nivolumab and ipilimumab (Arm B).

While the overall survival (OS) was less than 12 months for both treatment arms, Arm A showed a promising 2-year OS rate, indicating potential long-term benefits for some patients despite the overall limited efficacy of the treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01. Sahai, V., Griffith, KA., Beg, MS., et al.[2023]

Pembrolizumab, an immunotherapy drug, has shown remarkable efficacy in completely resolving tumors in two cases of advanced biliary tract cancers (BTC) after progression on standard treatment with gemcitabine and cisplatin.

This suggests that pembrolizumab may be a promising option for patients with advanced BTC who have not responded to conventional therapies, although further research is needed to establish its effectiveness in larger populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Completely resolved advanced biliary tract cancer after treatment by pembrolizumab: a report of two cases. Alshari, OM., Dawaymeh, TA., Tashtush, NA., et al.[2020]

Durvalumab, an anti-PD-L1 antibody, has been shown to improve overall survival in patients with advanced biliary tract cancers when combined with chemotherapy, based on results from a randomized phase III trial.

Future research is focusing on new combinations of immunotherapy agents, such as those targeting CTLA-4 or OX40, which may enhance T-cell activation and lead to better treatment outcomes compared to current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? Serrano Uson Junior, PL., Bekaii-Saab, T.[2023]

In a phase 3 trial involving 1069 patients with advanced biliary tract cancer, the addition of pembrolizumab to the standard chemotherapy regimen of gemcitabine and cisplatin significantly improved median overall survival from 10.9 months to 12.7 months.

The combination treatment did not introduce new safety concerns, with similar rates of severe adverse events between the pembrolizumab and placebo groups, suggesting it could be a viable new option for patients with this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Kelley, RK., Ueno, M., Yoo, C., et al.[2023]

A comprehensive analysis of 161 trials involving 6,337 patients found that the standard gemcitabine platinum (GP) chemotherapy has a median overall survival of 9.5 months and a tumor control rate of 63.5%.

Newer treatment regimens, including triplet combinations of gemcitabine, fluoropyrimidine, and platinum (GFP) or gemcitabine with targeted therapies, showed significantly better tumor control and overall survival compared to the standard GP regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy and targeted therapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Eckel, F., Schmid, RM.[2022]

In a study of 29 patients with unresectable biliary tract cancer, the combination therapy of gemcitabine (GEM) and cisplatin (CDDP) demonstrated a disease control rate of 66.7%, indicating its effectiveness as a treatment option.

The therapy was found to be safe, with manageable adverse effects; the most common severe hematological toxicity was neutropenia (65.5%), but there were no cases of interstitial pneumonia reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience]. Muneta, M., Ohmura, Y., Takeda, Y., et al.[2023]

In a study of 96 patients with advanced biliary tract adenocarcinoma, the combination of S-1 and cisplatin (SP) showed comparable efficacy to gemcitabine and cisplatin (GP), with six-month progression-free survival rates of 34.7% for SP and 43.8% for GP.

Both treatment regimens had a similar safety profile, but GP was associated with higher rates of severe side effects like neutropenia and anemia, suggesting that SP may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma. Kang, MJ., Lee, JL., Kim, TW., et al.[2022]

In a study of 43 patients with unresectable biliary tract cancer, the combination of gemcitabine and cisplatin showed an overall response rate of 27.5%, indicating it has potential efficacy in treating this difficult-to-treat cancer.

The treatment was generally well-tolerated, with manageable side effects, including low rates of severe hematologic toxicity, suggesting that gemcitabine plus cisplatin could be a safe option for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Thongprasert, S., Napapan, S., Charoentum, C., et al.[2022]

In a study of 51 patients with PD-L1-positive biliary tract cancer (BTC) who were resistant to gemcitabine/cisplatin, pembrolizumab demonstrated a 9.8% partial response rate and a median overall survival of 6.9 months, indicating its potential efficacy in this challenging cancer type.

The treatment was generally well-tolerated, with 58.8% of patients experiencing adverse events, but only 7.8% had severe (grade 3 or 4) adverse events, suggesting that pembrolizumab has manageable safety profiles in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Pembrolizumab for Gemcitabine/Cisplatin-Refractory Biliary Tract Cancer: A Multicenter Retrospective Study. Lee, SH., Lee, HS., Lee, SH., et al.[2020]

Citations

1. keytrudahcp.com keytrudahcp.com/efficacy/advanced-biliary-tract-cancer-combination-therapy/

KEYNOTE-966 - Clinical Trial Results | HCP Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37075781/

a randomised, double-blind, placebo-controlled, phase 3 trial We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04003636

Study Details | NCT04003636 | Pembrolizumab (MK-3475) ... The primary hypothesis is pembrolizumab plus gemcitabine/cisplatin is superior to placebo plus gemcitabine/cisplatin with respect to overall survival (OS).

4. ccanewsonline.com ccanewsonline.com/special-issues/2023-year-in-review-cca/keynote-966-pembrolizumab-combined-with-gemcis-versus-gemcis-alone-in-patients-with-btc

KEYNOTE-966: Pembrolizumab Combined With GemCis ... In the KEYNOTE-966 study, pembrolizumab was added to gemcitabine/cisplatin to assess outcomes in patients with advanced biliary tract cancer.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-05889

Pembrolizumab in Combination with Gemcitabine and ... This phase II trial compares the effect of pembrolizumab in combination with standard of care chemotherapy drugs, cisplatin and gemcitabine, for high-risk ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0168827825002077

Health-related quality of life in participants with advanced ... Kelley et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11171222/

A Systematic Review and Meta-Analysis - PubMed Central - NIH This study addresses the challenge of interpreting the efficacy of immunotherapy in biliary tract cancer (BTC) in terms of overall survival (OS) ...