Durvalumab + Chemotherapy for Biliary Tract Cancer

(TOURMALINE Trial)

Recruiting at 33 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

Trial Summary

What is the purpose of this trial?

A study to assess the safety and efficacy of durvalumab in combination with gemcitabine-based chemotherapy regimens in participants with aBTC.

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.

What data supports the effectiveness of the drug Durvalumab + Chemotherapy for Biliary Tract Cancer?

Research shows that adding Durvalumab to gemcitabine and cisplatin significantly improves survival in advanced biliary tract cancer patients, as seen in the TOPAZ-1 trial. Additionally, nab-paclitaxel combined with other drugs has shown promise in treating this type of cancer. ^{1 2 3 4 5}

Is the combination of Durvalumab and chemotherapy safe for humans?

The combination of Durvalumab with chemotherapy drugs like gemcitabine and cisplatin has been found to be generally manageable in terms of safety for patients with advanced biliary tract cancer. Studies have shown that this treatment can be tolerated by patients, although it is important to monitor for side effects. ^{1 2 3 6 7}

What makes the drug Durvalumab combined with chemotherapy unique for treating biliary tract cancer?

Durvalumab, when combined with gemcitabine and cisplatin, offers a new treatment option for advanced biliary tract cancer by blocking the PD-L1 protein, which helps the immune system fight cancer more effectively. This combination has been shown to significantly improve survival rates compared to standard chemotherapy alone. ^{1 7 8 9 10}

Eligibility Criteria

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.

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

Active or prior documented autoimmune or inflammatory disorders

Timeline

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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]

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 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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

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

2. China (Republic : 1949- ) 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. [2023]

3. Korea (South) 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. [2023]

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

Phase I study of weekly palliative chemotherapy with low-dose third-line paclitaxel for biliary tract cancer. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

6. 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]

7. 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]

8. England 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. [2023]

9. Netherlands 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. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of durvalumab plus chemotherapy as first-line treatment for biliary tract cancer. [2023]