Chemo + Immuno + Radiation Therapy for Bile Duct Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Andrea J Bullock, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

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.

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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.

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Beth Israel Deaconess Medical Center Boston, MA

Who Is Running the Clinical Trial?

Beth Israel Deaconess Medical Center Lead Sponsor

AstraZeneca Industry Sponsor

Sirtex Medical Industry Sponsor

Dana-Farber Cancer Institute Collaborator

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] The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting.

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

Durvalumab: A Review in Advanced Biliary Tract Cancer. [2023] Durvalumab (Imfinzi®), a therapeutic human monoclonal antibody which binds to and blocks the activity of the immunosuppressive programmed death-ligand 1 (PD-L1) protein, is approved in the USA, EU, Japan and other countries in combination with gemcitabine and cisplatin for adults with advanced biliary tract cancer. In the pivotal phase 3 TOPAZ-1 trial, durvalumab plus gemcitabine and cisplatin significantly prolonged overall survival and progression-free survival compared with placebo plus gemcitabine and cisplatin in adults with advanced biliary tract cancer. Benefit from durvalumab was seen irrespective of primary tumour location, disease status at diagnosis (unresectable or recurrent), or initial levels of PD-L1 expression. The tolerability of durvalumab plus gemcitabine and cisplatin was manageable. Overall, the addition of durvalumab to gemcitabine and cisplatin is a valuable new treatment option for adults with advanced biliary tract cancer.

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

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience]. [2023] Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer.

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] This study aimed to determine the maximum tolerated dose and the recommended dose of combining S-1 with gemcitabine and cisplatin for advanced biliary tract adenocarcinoma first-line therapy.

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

An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma. [2022] Label="INTRODUCTION" NlmCategory="UNASSIGNED">The combination of gemcitabine and cisplatin remains the standard-of-care first-line therapeutic option in patients with the unresectable disease based on the encouraging phase II and phase III trials (ABC-02). Recently, the combination of durvalumab, gemcitabine, and cisplatin has shown modest but statistically significant improvement in median overall survival (OS) as compared to that of the gemcitabine-cisplatin combination. Systemic therapy options such as the combination of 5-flurouracil (5-FU) and oxaliplatin (FOLFOX), 5-FU and liposomal irinotecan, and trifluridine/tipiracil (TAS-102) and irinotecan have shown encouraging results. Therapies targeting FGFR2 fusions/rearrangements, BRAF mutations, microsatellite high tumors, HER2 amplifications, and IDH mutations are currently being extensively evaluated in cholangiocarcinoma with encouraging results.

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] We conducted a phase I study for adjuvant chemotherapy of gemcitabine (GEM) plus S-1 in order to determine the maximum tolerated dose and the recommended dose (RD) and to evaluate the efficacy and toxicity of the regimen in curatively resected patients with biliary cancer.

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] The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in.

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

Immune checkpoint inhibitors in cholangiocarcinoma. [2023] Cholangiocarcinoma is an epithelial malignancy originating in the biliary tracts and frequently recurs even with surgical resection. Unresectable disease has a 5-year overall survival of less than 10%. Given this poor prognosis, additional therapies are urgently needed. Chemotherapy has been the mainstay of treatment for many years. However, with the incorporation of immunotherapy into the treatment of other malignancies, there has been a great deal of interest in immunotherapy for biliary cancers. Recently, durvalumab was approved in combination with gemcitabine and cisplatin for the treatment of unresectable cholangiocarcinoma in the first-line setting. However, predicting which patients may respond to immunotherapy remains a challenge due to the lack of a reliable biomarker.

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

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy. [2023] Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, and in vivo T-cell depletion and CD8+ T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+ T-cells. Depletion of CD8+ but not CD4+ T-cells compromised efficacy. Conversely, CD8+ T-cell transfer from Cxcr3-/- versus Cxcr3+/+ mice into Rag1-/- immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 "priming") with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.