Durvalumab + Chemotherapy for Biliary Tract Cancer

(TOURMALINE Trial)

Recruiting at 40 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Antidepressants, Biologics, Hormonal therapy, others

Disqualifiers: Uncontrolled hypertension, Active infection, Autoimmune disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

142 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of combining durvalumab, a type of immunotherapy, with chemotherapy for treating advanced biliary tract cancer, which affects the bile ducts, gallbladder, and liver. Researchers seek to determine if this combination can manage the cancer more effectively than current treatments alone. People with advanced biliary tract cancer that cannot be removed by surgery might be suitable candidates, especially if they have measurable tumors. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to access potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot have any concurrent chemotherapy or other cancer treatments besides the ones allowed in the study.

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

Research shows that combining durvalumab with gemcitabine-based chemotherapy is generally safe for adults with advanced biliary tract cancer. In earlier studies, patients found the side effects manageable. Specifically, when used with gemcitabine and cisplatin, the treatment proved effective and did not cause any unexpected severe side effects. Common side effects may include tiredness and nausea, typical of many cancer treatments. Overall, evidence supports the safety of this treatment approach. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for biliary tract cancer, which typically involve traditional chemotherapy drugs like cisplatin and gemcitabine, the investigational treatment combines durvalumab with gemcitabine-based chemotherapy. Durvalumab is a type of immunotherapy known as a PD-L1 inhibitor, which works by helping the immune system recognize and attack cancer cells more effectively. This approach is exciting because it offers the potential to enhance the body's natural defenses against cancer, possibly leading to better outcomes than chemotherapy alone. Additionally, the flexibility in treatment after the initial cycles allows for continued use of durvalumab, potentially maintaining its benefits while minimizing side effects. Researchers are hopeful that this combination will provide a more effective and durable response for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for biliary tract cancer?

In this trial, participants will receive a combination of durvalumab with gemcitabine-based chemotherapy. Research has shown that this combination extends the lives of people with advanced biliary tract cancer (aBTC). Specifically, the TOPAZ-1 trial demonstrated that patients using this combination lived longer than those who only received chemotherapy. In some trials, 72% of patients experienced tumor shrinkage, known as the objective response rate. Additionally, the treatment halted cancer growth in over 71% of patients, known as the disease control rate. These findings suggest that this treatment combination can effectively manage aBTC. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults over 30 kg with advanced biliary tract cancers, including cholangiocarcinoma, gallbladder carcinoma, and ampulla of Vater carcinoma. They should be able to perform daily activities (ECOG PS 0-2) and have at least one measurable tumor. Women must not be pregnant and all participants must use contraception. People with brain metastases, active infections like HIV or hepatitis, severe diseases, recent major surgeries or certain cancer treatments can't join.

Inclusion Criteria

I can take care of myself and am up and about more than 50% of my waking hours.

My partner and I are using birth control or are surgically sterile.

Negative pregnancy test (serum) for women of childbearing potential

Exclusion Criteria

I have had cancer spread to the lining of my brain and spinal cord.

Active or prior documented autoimmune or inflammatory disorders

I do not have severe illnesses like uncontrolled high blood pressure, active infections, or serious heart conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive up to 8 cycles of gemcitabine-based chemotherapy regimens with durvalumab

24 weeks

8 visits (in-person)

Maintenance Treatment

Participants continue receiving durvalumab alone or in combination with gemcitabine-based chemotherapy

Long-term

Follow-up

Participants are monitored for safety and survival after treatment

33 months

What Are the Treatments Tested in This Trial?

Interventions

• Albumin-bound Paclitaxel
• Carboplatin
• Cisplatin
• Durvalumab
• Gemcitabine
• Oxaliplatin
• S-1

Trial Overview The study tests the safety and effectiveness of durvalumab combined with various gemcitabine-based chemotherapy regimens in patients with advanced biliary tract cancers. Durvalumab is an immunotherapy drug given alongside standard chemotherapies like cisplatin or oxaliplatin to see if it improves outcomes.

How Is the Trial Designed?

Group I: Durvalumab + Gemcitabine based chemotherapy Experimental Treatment 8 Interventions

Participants will receive durvalumab 1500mg every 3 or 4 weeks, in combination with continuation of all or some of the original background gemcitabine based chemotherapy every 3 or 2 weeks for up to a maximum of 8 cycles of chemotherapy. Durvalumab 1500mg is given as a 60-minute IV infusion in the first cycle (Day 1) and as a 30-minute IV infusion in following cycles. Upon completing 8 cycles of background gemcitabine-chemotherapy, or after discontinuing any of the combination chemotherapies due to toxicity before completing 8 cycles, participants are eligible to continue receiving durvalumab 1500 mg IV every 4 weeks either alone or in combination with gemcitabine-based chemotherapy (with the exception of paclitaxel), as per investigator's discretion.

Albumin-bound Paclitaxel is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Abraxane for:

• Breast cancer
• Pancreatic cancer
• Non-small cell lung cancer

Approved in United States as Abraxane for:

• Metastatic breast cancer
• Locally advanced or metastatic non-small cell lung cancer
• Advanced pancreatic cancer

Approved in Canada as Abraxane for:

• Breast cancer
• Non-small cell lung cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

Published Research Related to This Trial

The TOPAZ-1 trial demonstrated that durvalumab combined with chemotherapy significantly improves survival in patients with biliary tract cancer, but this treatment is not cost-effective compared to placebo plus chemotherapy, with high incremental cost-effectiveness ratios (ICERs) of $381,864.39/QALY in the US and $367,608.51/QALY in China.

Despite the survival benefits, the analysis indicates that neither US nor Chinese payers would find durvalumab plus chemotherapy a cost-effective option for first-line treatment of biliary tract cancer, as the likelihood of it being cost-effective was 0% under the respective willingness-to-pay thresholds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of durvalumab plus chemotherapy as first-line treatment for biliary tract cancer. Ye, ZM., Xu, Z., Li, H., 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 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]

Adding durvalumab to gemcitabine and cisplatin for advanced biliary tract cancer resulted in only a modest increase in quality-adjusted life years (0.12 QALY) but came with a high incremental cost, leading to an incremental cost-effectiveness ratio (ICER) of $159,644.70/QALY with charity assistance and $696,571.11/QALY without, both exceeding the willingness-to-pay threshold in China.

The analysis indicated that durvalumab would only become cost-effective if its price dropped by over 94.2%, highlighting that the high cost of durvalumab significantly impacts its economic viability as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of adding durvalumab to chemotherapy as first-line treatment for advanced biliary tract cancer based on the TOPAZ-1 trial. Zhao, Q., Xie, R., Zhong, W., et al.[2023]

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]

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]

The combination of nab-paclitaxel and S-1 demonstrated a 27.5% objective response rate in patients with advanced biliary tract carcinoma, indicating significant antitumor activity, especially in gallbladder carcinoma (53.8% response).

The treatment showed a favorable safety profile, with the most common severe side effects being neutropenia and stomatitis, and median progression-free survival and overall survival were 6.0 months and 13.2 months, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial. Zhang, W., Sun, Y., Jiang, Z., et al.[2023]

In a study of 34 patients with advanced biliary tract cancer, the combination of nab-paclitaxel, gemcitabine, and cisplatin resulted in a median progression-free survival of 7.1 months and overall survival of 16.4 months, indicating promising therapeutic potential.

The treatment was associated with significant adverse effects, particularly neutropenia and leukopenia in 26.5% of patients, while biomarkers like carcinoembryonic antigen (CEA) levels and immune cell changes were identified as potential indicators of treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Single-Arm Phase II Study of Nab-Paclitaxel Plus Gemcitabine and Cisplatin for Locally Advanced or Metastatic Biliary Tract Cancer. Liu, T., Li, Q., Lin, Z., et al.[2023]

A phase I clinical trial of low-dose paclitaxel (PTX) as third-line palliative chemotherapy for patients with unresectable biliary tract cancer showed it was well-tolerated, with no severe adverse events (grade 3 or 4) reported.

The treatment resulted in a disease control rate of 83.3% and a median overall survival of 9.0 months, indicating that low-dose PTX is both safe and effective for patients who have not responded to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer. Tajima, H., Ohta, T., Shinbashi, H., et al.[2020]

In a phase 2 study involving 128 patients with advanced biliary tract cancer, the combination of gemcitabine and cisplatin with the immunotherapy durvalumab (and tremelimumab for some) resulted in a promising objective response rate of 66%, indicating potential efficacy as a first-line treatment.

The treatment was generally safe, with the most common severe side effects being decreased neutrophil count and anemia, but no unexpected safety events or treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study. Oh, DY., Lee, KH., Lee, DW., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39566070/

Real-world effectiveness and prognostic factors of ... The TOPAZ-1 trial of durvalumab plus first-line chemotherapy (gemcitabine plus cisplatin) showed improved survival vs chemotherapy alone. This ...

2. academic.oup.com academic.oup.com/oncolo/article/30/8/oyae306/7905746

Real-world effectiveness and prognostic factors of durvalumab ... The TOPAZ-1 trial of durvalumab plus first-line chemotherapy (gemcitabine plus cisplatin) showed improved survival vs chemotherapy alone.

3. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2200015

Durvalumab plus Gemcitabine and Cisplatin in Advanced ... A phase 2 trial of durvalumab in combination with gemcitabine and cisplatin demonstrated promising efficacy, with an objective response rate of 72% and a ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11447177/

Exploring the impact of durvalumab on biliary tract cancer Results. Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.598

Durvalumab (DUR) effectiveness in advanced biliary tract ... Based on TOPAZ-1 trial, Durvalumab (DUR) plus gemcitabine and cisplatin significantly improved overall survival (OS) in advanced biliary tract cancer (aBTC) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10667376/

Durvalumab: A Review in Advanced Biliary Tract Cancer The tolerability of durvalumab plus gemcitabine and cisplatin was manageable in adults with advanced biliary tract cancer in the TOPAZ-1 trial [ ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03046862

NCT03046862 | Durvalumab(MEDI4736)/Tremelimumab in ... The combination of Durvalumab/Tremelimumab with gemcitabine/cisplatin chemotherapy is feasible and efficacious in chemo-naïve biliary tract cancer.

8. touchoncology.com touchoncology.com/gastrointestinal-cancers/journal-articles/durvalumab-for-the-treatment-of-advanced-biliary-tract-cancer/

Durvalumab for the Treatment of Advanced Biliary Tract ... After 41 months, the survival rate at 36 months was 14.6% with durvalumab plus GemCis compared with 6.9% with GemCis alone. The combination was ...

9. asco.org asco.org/abstracts-presentations/ABSTRACT434862

Phase I/II clinical trial of regorafenib plus durvalumab ... The hazard ratio for progression-free survival favored durvalumab at 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates also showed improvement, ...