Pembrolizumab + Chemotherapy for Bile Duct Cancer

Overseen By Hop Tran Cao, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Uncontrolled illness, Active infection, 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: 6

Duration: 9 months

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding pembrolizumab, an immunotherapy drug, to standard chemotherapy enhances the effectiveness of bile duct cancer treatments post-surgery. The researchers will assess whether this combination improves long-term patient response compared to standard treatment alone. Candidates for this study include those with intrahepatic cholangiocarcinoma, a type of bile duct cancer that remains operable but is considered high-risk. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 certain treatments like systemic steroids or immunosuppressive therapy, you may need to adjust them before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that adding pembrolizumab to the chemotherapy drugs gemcitabine and cisplatin is generally well-tolerated. Studies have demonstrated that this combination improves survival rates for patients with advanced biliary tract cancer. Pembrolizumab, also known as Keytruda, helps the immune system find and attack cancer cells.

In these studies, some patients experienced side effects. The most common were tiredness, nausea, and loss of appetite. Serious side effects were less common but included low blood cell counts, liver issues, and effects on the immune system. Medical care mostly managed these side effects.

Overall, the combination of pembrolizumab with gemcitabine and cisplatin has shown promise in both safety and effectiveness. Prospective participants should discuss these findings with their doctor to understand what to expect. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for bile duct cancer?

Researchers are excited about combining Pembrolizumab with chemotherapy for bile duct cancer because it represents a potential leap forward in treatment. Unlike standard options that primarily rely on chemotherapy alone, Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. This combination aims to enhance the body's natural defenses while simultaneously using chemotherapy to target the cancer, potentially leading to more effective outcomes. By integrating these approaches, there's hope for improved survival rates and better management of this challenging condition.

What evidence suggests that pembrolizumab with chemotherapy could be effective for bile duct cancer?

Research has shown that adding pembrolizumab to the standard chemotherapy drugs, gemcitabine and cisplatin, can benefit people with bile duct cancer. The KEYNOTE-966 study demonstrated that this combination extended patients' lives compared to chemotherapy alone. In this trial, participants will receive pembrolizumab with gemcitabine and cisplatin. Another study found that pembrolizumab remains effective over time in patients whose cancer does not respond to gemcitabine and cisplatin. This treatment shows particular promise for those with advanced bile duct cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Hop Tran Cao, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults diagnosed with intrahepatic cholangiocarcinoma that can potentially be removed by surgery. They should not have had previous systemic therapy for this cancer, no other active cancers or serious illnesses, and must agree to use contraception. HIV-positive patients on effective treatment can join.

Inclusion Criteria

Adequate hematologic status: ANC ≥ 1.5 x 10^9/L; Hgb ≥ 9 g/dL; PLT ≥ 100 x 10^9/L

HCV viral load undetectable at screening

Willing and able to participate in the trial and comply with all trial requirements

Exclusion Criteria

I do not have any uncontrolled illnesses like heart failure or recent heart attacks.

I have been treated with drugs targeting immune checkpoints.

I have received systemic therapy for bile duct cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab with gemcitabine and cisplatin for 4 cycles (21 days each) before and after surgery

9 months

Clinic visits every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 years

Clinic visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Gemcitabine
• Pembrolizumab

Trial Overview The trial is testing if adding pembrolizumab (an immunotherapy drug) to the usual chemotherapy drugs gemcitabine and cisplatin before and after surgery can improve outcomes in bile duct cancer compared to just surgery and chemotherapy.

How Is the Trial Designed?

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

Participants will receive 4 cycles (21 days each) of the combined chemotherapy before and after your scheduled surgery. During the 9 months of chemotherapy treatment, participants will have clinic visits every 3 weeks or so. During the 2-4 year follow-up period, participants will come to the clinic every 3 months or so

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

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]

In a study of 42 patients with inoperable or metastatic cholangiocarcinoma, the combination of gemcitabine and cisplatin showed a response rate of 21%, with a median survival of 10.8 months and a progression-free survival of 8.5 months.

The treatment was generally well-tolerated, with no treatment-related deaths and only mild non-hematologic toxicities, although 33% of patients experienced grade 3-4 anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with gemcitabine and cisplatin in the therapy of inoperable and metastatic cholangiocarcinoma. Charoentum, C., Thongprasert, S., Chewaskulyong, B., et al.[2022]

In a study of 29 patients with biliary tract cancer, the combination therapy of gemcitabine and cisplatin was found to be tolerable, with 72% of patients completing the treatment protocol despite some experiencing significant side effects like leukopenia and neutropenia.

The two-year recurrence-free survival rate was 59% and the overall survival rate was 90%, suggesting that this treatment regimen may be effective in improving survival outcomes for patients after curative resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and efficacy of gemcitabine plus cisplatin combination therapy after curative resection for biliary tract cancer. Kainuma, O., Miura, F., Furukawa, D., et al.[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 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]

Pembrolizumab (PEM), an anti-PD-1 antibody, was successfully used to treat a 57-year-old man with microsatellite instability-high (MSI-high) locally advanced cholangiocarcinoma after conventional chemotherapy failed, demonstrating its potential efficacy in this rare cancer type.

After 15 cycles of PEM treatment over approximately 10 months, the patient's tumor size decreased significantly, and tumor markers showed dramatic improvement, indicating a positive response to this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of pembrolizumab in microsatellite instability-high locally advanced cholangiocarcinoma: a case report. Toshida, K., Itoh, S., Yoshizumi, T., et al.[2021]

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 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 150 patients with advanced biliary cancers, the addition of cetuximab to standard chemotherapy (gemcitabine and oxaliplatin) did not significantly improve progression-free survival compared to chemotherapy alone, with median progression-free survival of 6.1 months versus 5.5 months, respectively.

While cetuximab was well tolerated, the study found a higher incidence of grade 3-4 adverse events in the cetuximab group, suggesting that the standard chemotherapy regimen should remain the preferred treatment for advanced biliary cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Malka, D., Cervera, P., Foulon, S., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4093

Three-year follow-up data from KEYNOTE-966 KEYNOTE-966 demonstrated that adding pembro to gem/cis provided a statistically significant, clinically meaningful improvement in OS as first-line therapy for ...

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

KEYNOTE-966 - Clinical Trial Results | HCP The efficacy of KEYTRUDA in combination with gemcitabine/cisplatin chemotherapy was investigated in KEYNOTE-966, a multicenter, randomized, double-blind ...

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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7355970/

Efficacy and Safety of Pembrolizumab for Gemcitabine/ ... In PD-L1-positive gemcitabine/cisplatin-refractory BTC, pembrolizumab presented durable efficacy, with a 9.8% response rate and manageable toxicity.

5. cell.com cell.com/heliyon/fulltext/S2405-8440(25)00933-8

Cost-effectiveness analysis of pembrolizumab combined ... This study aims to assess the economic feasibility of incorporating pembrolizumab in combination with gemcitabine and cisplatin (GC) as the first-line therapy

6. 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 ...

7. 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).

8. 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 ...