Chemo + Immuno + Radiation Therapy for Bile Duct Cancer

Overseen By Andrea J Bullock, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Beth Israel Deaconess Medical Center

Must not be taking: Immunosuppressants, Anti-PD-1

Disqualifiers: Hepatocellular carcinoma, Heart failure, Autoimmune disorders, 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: 1

Duration: 8 cycles of 21 days each

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is designed to study a combination of interventions (chemotherapy, immunotherapy, and radiation) as a potential new treatment for bile duct cancer that cannot be removed with surgery. The specific names of the interventions that will be used are: * Y-90 (a type of radiation microsphere bead) * Durvalumab (a type of immunotherapy) * Gemcitabine (a type of chemotherapy) * Cisplatin (a type of chemotherapy)

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 medications that interact with the trial drugs, especially those affecting the immune system or with overlapping toxicities, you may need to adjust your treatment. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of this treatment for bile duct cancer?

Research shows that combining durvalumab with gemcitabine and cisplatin significantly improves survival in patients with advanced biliary tract cancer. This combination has been shown to be more effective than gemcitabine and cisplatin alone, offering a valuable new treatment option. ^{1 2 3 4 5}

Is the combination of chemo, immuno, and radiation therapy safe for bile duct cancer?

The combination of durvalumab (an immune therapy), gemcitabine, and cisplatin (both chemotherapy drugs) has been studied in patients with advanced biliary tract cancer, and the safety was found to be manageable. This combination is approved in several countries and has shown a survival benefit in clinical trials. ^{1 2 4 6 7}

What makes the treatment with Cisplatin, Durvalumab, Gemcitabine, and Yttrium-90 unique for bile duct cancer?

This treatment combines chemotherapy, immunotherapy, and radiation, offering a novel approach by using durvalumab, an immunotherapy drug that blocks a protein called PD-L1, alongside traditional chemotherapy drugs cisplatin and gemcitabine, which has shown improved survival in advanced biliary tract cancer. The addition of Yttrium-90, a form of radiation therapy, may further enhance the treatment's effectiveness by directly targeting cancer cells. ^{1 2 5 8 9}

Research Team

Andrea J Bullock, MD

Principal Investigator

Beth Israel Deaconess Medical Center

Eligibility Criteria

Adults with advanced bile duct cancer that can't be surgically removed may join this trial. They must understand and agree to the study's terms, have a certain level of physical fitness (ECOG ≤1), weigh over 30 kg, and have proper liver, kidney, and bone marrow function. People with active hepatitis or HIV are excluded unless meeting specific conditions. Those who've had recent immunotherapy or certain infections, or are pregnant/breastfeeding cannot participate.

Inclusion Criteria

I do not have an active hepatitis B or C infection.

Body weight >30 kg

Adequate coagulation studies as demonstrated by prothrombin (PT) and partial thromboplastin (PTT) time within normal limits in the absence of anticoagulation medication

Exclusion Criteria

I have HIV, HBV, or HCV that is not being treated.

I do not have any active, uncontrolled infections.

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Gemcitabine, Cisplatin, and Durvalumab with Y-90 radiation in Cycle 1, followed by multiple cycles of chemotherapy and immunotherapy

8 cycles of 21 days each

Multiple visits per cycle

Maintenance

Participants receive Durvalumab (immunotherapy) maintenance therapy

Until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 52 weeks

Regular follow-up visits

Treatment Details

Interventions

• Cisplatin
• Durvalumab
• Gemcitabine
• Yttrium-90

Trial Overview The trial is testing a combination therapy for bile duct cancer involving Y-90 radiation beads, Durvalumab immunotherapy, and Gemcitabine plus Cisplatin chemotherapy. It aims to see if this mix can effectively treat patients whose cancer has not been removed by surgery.

Participant Groups

Group I: Gemcitabine + Cisplatin + Durvalumab + Yttrium-90 Selective Internal Radiation Therapy Experimental Treatment 4 Interventions

Participants will receive: * Cycle 1: Day 1 of 21 Day cycle: Pre-determined dose(s) of Gemcitabine and Cisplatin (Chemotherapy) plus Durvalumab (immunotherapy). Day 8 of 21 Day cycle: Pre-determined dose(s) of Gemcitabine and Cisplatin (Chemotherapy) Week 2 or 3 of 21 Day Cycle: One time treatment of Y-90 radiation. * Cycles 2-8: Day 1 of 21 Day cycle: Pre-determined dose(s) of Gemcitabine and Cisplatin (Chemotherapy) plus Durvalumab (immunotherapy). Day 8 of 21 Day cycle: Pre-determined dose(s) of Gemcitabine and Cisplatin (Chemotherapy) * Cycles 9+: Day 1 of 21 Day Cycle: Durvalumab (immunotherapy) maintenance

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?

Beth Israel Deaconess Medical Center

Lead Sponsor

Trials

872

Recruited

12,930,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Sirtex Medical

Industry Sponsor

Trials

30

Recruited

4,300+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Findings from Research

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 the phase 3 TOPAZ-1 trial, the combination of durvalumab with gemcitabine and cisplatin significantly improved overall survival and progression-free survival in adults with advanced biliary tract cancer, compared to the placebo group.

Durvalumab's benefits were consistent across various patient factors, including tumor location and PD-L1 expression levels, and the treatment was found to be manageable in terms of tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Advanced Biliary Tract Cancer. Fung, S., Syed, YY.[2023]

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]

The study established that the maximum tolerated dose and recommended dose for the combination of S-1, gemcitabine, and cisplatin in treating advanced biliary tract adenocarcinoma is level 0: gemcitabine at 800 mg/m²/week, cisplatin at 25 mg/m²/week, and S-1 at 40 mg/m²/day, based on treatment of 17 patients.

The treatment regimen was well tolerated, with some dose-limiting toxicities observed, and it demonstrated promising antitumor activity, with five partial responses noted among the participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer. Shoji, H., Morizane, C., Sakamoto, Y., et al.[2022]

The combination of durvalumab with gemcitabine and cisplatin has shown a statistically significant improvement in median overall survival compared to the standard gemcitabine-cisplatin treatment in patients with unresectable cholangiocarcinoma.

Ivosidenib is a promising treatment for patients with IDH1-mutant cholangiocarcinoma who have progressed on first-line chemotherapy, offering excellent tolerability and a median overall survival benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma. Tella, SH., Mahipal, A.[2022]

In a phase I study involving 34 patients with biliary cancer, the maximum tolerated doses for the chemotherapy regimen of gemcitabine and S-1 were determined, with specific doses recommended based on the type of surgery: GEM 1,000 mg/m² + S-1 80 mg/m² after pancreatoduodenectomy and GEM 800 mg/m² + S-1 60 mg/m² after hemihepatectomy.

The most significant side effects observed were hematological toxicities, particularly neutropenia and thrombocytopenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in curatively resected patients with biliary tract cancer: adjusting the dose of adjuvant chemotherapy according to the surgical procedures. Takahara, T., Nitta, H., Hasegawa, Y., et al.[2022]

In the safety run-in of the IMMUNOBIL PRODIGE 57 trial involving 20 patients, the combination of durvalumab and tremelimumab with paclitaxel resulted in a high rate of dose-limiting toxicities (50%), including serious anaphylactic reactions and other severe adverse events.

Due to the safety concerns raised by the combination therapy, the trial will proceed with only the durvalumab and tremelimumab combination, indicating that the addition of paclitaxel may not be safe for patients with advanced biliary tract carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Boilève, A., Hilmi, M., Gougis, P., et al.[2021]

Durvalumab, an immunotherapy drug, has been approved for use with gemcitabine and cisplatin as a first-line treatment for unresectable cholangiocarcinoma, which has a very low 5-year survival rate of less than 10%.

Despite the promising combination therapy, identifying which patients will benefit from immunotherapy remains difficult due to the absence of a reliable biomarker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors in cholangiocarcinoma. Beri, N.[2023]

Combining gemcitabine/cisplatin chemotherapy with anti-PD1 and anti-CTLA-4 immunotherapy significantly improved survival and reduced disease severity in aggressive intrahepatic cholangiocarcinoma (ICC) models, which were previously resistant to immunotherapy.

The treatment enhanced T-cell infiltration and normalized tumor vasculature, with CD8+ T-cells being crucial for the efficacy of the combination therapy, suggesting a promising strategy to improve outcomes for ICC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy. Chen, J., Amoozgar, Z., Liu, X., et al.[2023]

References

1. 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]

2. France pubmed.ncbi.nlm.nih.gov

Durvalumab: A Review in Advanced Biliary Tract Cancer. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience]. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in curatively resected patients with biliary tract cancer: adjusting the dose of adjuvant chemotherapy according to the surgical procedures. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors in cholangiocarcinoma. [2023]

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

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy. [2023]