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Advanced Biliary Tract CarcinomaPhase 2IMMUNO-BILNCT03704480

Durvalumab + Tremelimumab ± Paclitaxel in Advanced BTC After Platinum Chemotherapy.

A Phase 2 study testing Durvalumab and Tremelimumab in people with Advanced Biliary Tract Carcinoma, run by GERCOR - Multidisciplinary Oncology Cooperative Group at 28 sites in France.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

IMMUNO-BIL is a non-comparative randomized 1:1 phase II study. This study will assess the efficacy and safety of the combination of durvalumab plus tremelimumab with or without weekly paclitaxel in patients with advanced BTC after failure of platinum-based chemotherapy. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Biliary Tract Carcinoma
What is being tested?
Durvalumab and Tremelimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
106 participants
Where
28 sitesFrance
Study dates
9 Nov 2018to 31 Dec 2025
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
  • Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • Histologically or cytologically proven BTC (extrahepatic CCA, intrahepatic CCA, or gallbladder carcinoma).
  • Failure (documented progression or toxicity) of previous platinum-based (cisplatin or oxaliplatin) therapy (e.g. GEMCIS, GEMOX, FOLFIRINOX) Note: a maximum of 1 previous chemotherapy line is allowed; maintenance therapy with chemotherapy or targeted agent, except immunotherapy, will be permitted.
  • Age ≥ 18 years at the time of study entry.
  • ECOG PS 0-1.
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  • Recurrent or advanced disease not amenable to surgery, radiation, or combined modality therapy with curative intent (previous resection of primary tumor allowed).
  • Measurable or evaluable (radiologically detectable disease which does not fulfill RECIST criteria for measurable disease) lesions according to RECIST v1.1 criteria (CT-scan < 3 weeks).
  • Have tissue from an archival tissue sample that has been identified and confirmed as available for study, or newly obtained core or excisional biopsy of a tumor lesion.
  • Adequate organ function, as defined by the following:
  • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
  • Total serum bilirubin < 1.5 ULN
  • Prothrombin ratio > 70%
  • Serum albumin ≥ 28 g/L
  • Hemoglobin ≥ 9.0 g/dl
  • White blood cell count (WBC) ≥ 3,000/μL
  • Absolute neutrophil count (ANC) ≥ 1,500/μL
  • Platelets ≥ 100,000/μL
  • Serum creatinine ≤ 1.5 ULN or creatinine clearance > 50 mL/min (MDRD).
  • Body weight > 40 kg.
  • Any other prior therapy directed at the malignant tumor, including chemotherapy, chemoembolization therapy, molecular targeted therapy (including antiangiogenics), and radiotherapy, must be discontinued at least 2 weeks prior to registration and at least 3 weeks before day 1 on trial.
  • Life expectancy ≥ 3 months.
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Women participants of childbearing potential must have a negative serum pregnancy test within the 7 days prior to the first treatment administration. Both women participants of childbearing potential and men participants who are sexually active with women of childbearing potential must agree to use a reliable method of birth control (i.e. pregnancy rate < 1% per year); women of childbearing potential will be instructed to adhere to contraception for a period of 180 days after the last dose of durvalumab and tremelimumab or 90 days after the last dose of durvalumab monotherapy or 6 months after the last dose of paclitaxel. Men participants who are sexually active with women of childbearing potential will be instructed to adhere to contraception and must refrain from sperm donation for a period of 180 days after the last dose of durvalumab and tremelimumab or 90 days after the last dose of durvalumab monotherapy or 6 months after the last dose of paclitaxel.
  • Registration in a national health care system (PUMA included).

Who cannot join

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
  • Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) or supportive care clinical study or during the follow-up period of an interventional study.
  • Receipt of the last dose of anticancer therapy (investigational product, chemotherapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤ 21 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetics properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator.
  • Mixed histology (hepatocholangiocarcinoma).
  • Extensive tumor massively replacing both entire lobes.
  • Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage.
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  • Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • Patients with Grade ≥ 2 neuropathy will be excluded
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
  • History of allogenic organ transplantation.
  • Any systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent) whatever the duration of this corticotherapy
  • Note: The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies) Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [HBc] antibody test) are eligible.
  • Note: Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
  • Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or in situ carcinoma of the cervix uteri.
  • Prior treatment with taxane or any immune ICI, including durvalumab and tremelimumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody.
  • Known active central nervous system metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day of prednisone or equivalent for at least 14 days prior to trial treatment.
  • Uncontrolled massive pleural effusion or massive ascites.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]), that has required systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Note: Patients with vitiligo, alopecia, or any chronic skin condition that does not require systemic therapy are exception to this criterion.
  • Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
  • Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • Live vaccine administration within 30 days prior to the first dose of study treatment Note: Patients, if enrolled, should not receive live vaccine whilst receiving investigational product and up to 30 days after the last dose of investigational product.
  • Known or suspected allergy or hypersensitivity to any of the study drugs or any of the study drug excipients (taxane, durvalumab, or tremelimumab).
  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms.
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator.
  • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • Pregnancy/lactation.
  • Tutelage or guardianship.

Trial locations and contacts

28 sites in 1 country.

28 sites in 1 country

France28 sites

  • CHRU Jean Minjoz

    Besançon

  • Polyclinique Bordeaux Nord Aquitaine

    Bordeaux

  • Hôpital Duchenne

    Boulogne-sur-Mer

  • CHU Morvan

    Brest

  • Hôpital Beaujon

    Clichy

  • CHPSO Site de Creil

    Creil

  • CHU Henri Mondor

    Créteil

  • Centre Georges François Leclerc

    Dijon

  • CHU Dijon

    Dijon

  • Institut Andrée Dutreix

    Dunkirk

  • Institut Hospitalier franco-Britannique

    Levallois-Perret

  • CHRU Lille

    Lille

  • Centre Léon Bérard

    Lyon

  • Hôpital Privé Jean Mermoz

    Lyon

  • Hôpital la Timone

    Marseille

  • Hôpital Saint Eloi

    Montpellier

  • Hôpital Prive du confluent SAS

    Nantes

  • Hôpital Cochin

    Paris

  • Hôpital Saint Antoine

    Paris

  • Institut Mutualiste Montsouris

    Paris

  • Hôpital Haut Lévêque

    Pessac

  • CHU Poitiers

    Poitiers

  • CHU Robert Debré

    Reims

  • Centre Eugène Marquis

    Rennes

  • Institut Curie

    Saint-Cloud

  • CHI Poissy Saint Germain

    Saint-Germain-en-Laye

  • Centre Paul Strauss

    Strasbourg

  • Insitut Gustave Roussy

    Villejuif

Other trials in France

About this study

Official title: Durvalumab Plus Tremelimumab Combination Immunotherapy With or Without Weekly Paclitaxel in Patients With Advanced Biliary Tract Carcinoma (BTC) After Failure of Platinum-based Chemotherapy: a Randomized Non-comparative Two-arm Phase II Study

IMMUNO-BIL is a non-comparative randomized 1:1 phase II study. This study will assess the efficacy and safety of the combination of durvalumab plus tremelimumab with or without weekly paclitaxel in patients with advanced BTC after failure of platinum-based chemotherapy.

On the 25th June 2019, the maximum DLT event number was reached (6/10) in the durvalumab plus tremelimumab combination with paclitaxel Arm (Arm B). According to the Pocock boundary described in the protocol, GERCOR has updated the study to discontinue enrollment in Arm B (durvalumab plus tremelimumab with paclitaxel) . No safety concerns were raised by the IDMC in Arm A. Consequently, the study will resume with Arm A (durvalumab plus tremelimumab) only, without randomization.

Read more

Discontinuation of ARM B(June 2019): Durvalumab plus tremelimumab plus paclitaxel

One cycle equals 4 weeks (D1=D28); Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent.

Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles. Paclitaxel: 80 mg/m2, every week for 3 weeks (D1-D8-D15), by IV infusion, until progression or unacceptable toxicity or withdrawal of consent (at least 6 cycles, at the discretion of the investigator).

December 2020: Tremelimumab dosage modification based on the results of the Study 22 study (Kelley RK, et al. ASCO20 Virtual Scientific Program 2020) showing increased efficacy (response rate and progression-free survival) without safety concerns with one dose of tremelimumab 300 mg (cycle 1) instead of four doses of 75 mg (cycle 1 to cycle 4) in combination with durvalumab 1,500 mg Q4W in hepatocellular carcinoma. Following these results, we have changed the tremelimumab 75 mg x 4 schedule for the 300 mg x 1 schedule. The inclusion of 106 additional patients will be required to adequately evaluate the efficacy of this administration schedule.

ARM A : Durvalumab plus tremelimumab ( patients included before 31/12/2020) One cycle equals 4 weeks (D1=D28);

Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent.

Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles.

Read the detailed description

Biliary tract carcinoma (BTC, adenocarcinoma in more than 90% of cases) is the second primary liver tumor in incidence after hepatocellular carcinoma (2,000 new cases/year in France).

The prognosis of biliary malignancies is poor, with a 5-year overall survival rate (OS) of about 10-15%, most often due to late diagnosis, at an advanced stage.

In advanced BTC, the gemcitabine plus platinum (cisplatin [GEMCIS] or oxaliplatin [GEMOX]) doublet of chemotherapy is the standard first-line treatment and no targeted therapy has been validated in this indication to date. There is no second-line therapeutic standard; chemotherapy (mainly, 5-FU-based combination) yields limited median progression-free survival (PFS) and OS of abouty 2-3 months and 6-7 months respectively, justifying the exploration of new therapeutic options.

Immune therapies (mainly, immune checkpoint inhibitors [ICI]) have opened new opportunities in cancer therapy. Hence, anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb) have demonstrated robust clinical activity and obtained FDA approval in several cancers. Recent data showed encouraging results with anti-PD-1 mAb as a monotherapy in PD-L1-positive pre-treated advanced BTC. The effects of ICI in combination with second-line chemotherapy in patients with advanced BTC have not been explored to date.

Platinum salts can induce "immunogenic cell death". Therefore, previous treatment with platinum may increase tumor immunogenicity and sensitivity to immune therapy, particularly, ICI. The second-line setting after failure of platinum-based chemotherapy may then be an optimal biological context for testing immune therapy in advanced BTC.

Durvalumab is a human immunoglobulin (Ig) G1 kappa (IgG1κ) anti-PD-L1 mAb. Tremelimumab is a human IgG2 anti-CTLA-4 mAb. Paclitaxel is a chemotherapy belonging to the taxane family. Taxanes may enhance the effect of immunotherapy by increasing the sensitivity of the tumor and activating the immune system. Taxanes are used in some patients with advanced biliary cancer.

These data suggest that BTC may be a good candidate for immune therapy. The combination of anti-CTL4 and anti-PD1/PD-L1 mAb is expected to be active in both immune-inflamed and non-inflamed BTC, and in PD-L1 high and low tumors.

Keywords
Immunotherapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736

    1500mg by intravenous (IV) infusion on D1 until progression or unacceptable toxicity or withdrawal of consent

  • TremelimumabDrug

    Also called CP-675

    300mg by IV infusion on D1 at cycle 1 only

Study groups in NCT03704480
Study groupRoleWhat they receive
Amended ARM AExperimentalOne cycle equals 4 weeks (D1=D28); Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent. Tremelimumab: 300 mg by IV infusion on D1 at cycle 1 only.
Receives: Drug: Durvalumab; Drug: Tremelimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival (OS) in amended Arm A

    OS - defined as the time from date of randomization to date of death. In the absence of confirmation of death, survival time will be censored at the date of the last clinical assessment

    Measured: At 6 months

Secondary outcomes (8)

  1. Safety profile - All grade and severe (grade 3-5)

    All grade and severe (grade 3-5) adevrse events, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 5.0

    Measured: From signature of informed consent to 3 months after last study treatment administration

  2. RECIST v1.1 and iRECIST criteria in arm A and amended Arm A

    RECIST v1.1 and iRECIST criteria comparison for tumor response evaluation in arm A and amended Arm A

    Measured: At 2 months, evaluation every 2 months during treatment period and end of treatment (until the date of first documented progression or date of death, assessed up to 30 months

  3. Health-related Quality of life (HRQoL) assessed by EORTC QLQ-C30 questionnaire in Arm A and amended Arm A

    A quality of life score is obtained according to the answers to the questionnaires.

    Measured: Baseline, every 2 months during treatment period and end of treatment (until the date of first documented progression or date of death)

  4. Health-related Quality of life (HRQoL) assessed by EORTC QLQ-BIL21 questionnaire

    A quality of life score is obtained according to the answers to the questionnaires.

    Measured: Baseline, every 2 months during treatment period and end of treatment (until the date of first documented progression or date of death)

  5. Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment (Q-Twist) in arm A and amended Arm A

    Q-TWiST analysis considers three health states, TOX, TWiST, and REL, and the duration of each state is calculated for every patient.

    Measured: assessed up to 30 months

  6. Predictive markers of response in arm A and amended arm A

    Evaluation of predictive markers of response in arm A and amended arm A

    Measured: Baseline, Month 2, Month 4, Month 8, Month 12, Month 18, Month 24 and end of study (until the date of first documented progression or date of death, assessed up 30 months

  7. Progression free survival (PFS) in Arm A and Amended Arm A

    PFS at 4 months according to iRECIST (centralized review of CT-scan imaging) Note: disease progression on CT-scan imaging must be confirmed by a new imaging at 4 weeks in order to meet iRECIST criteria.

    Measured: at 4 months

  8. Overall Survival (OS) in Arm A

    OS - defined as the time from date of randomization to date of death. In the absence of confirmation of death, survival time will be censored at the date of the last clinical assessment

    Measured: At 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Oct 2018
  2. Study start9 Nov 2018
  3. Primary completion28 Jul 2022
  4. Study completion31 Dec 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
106 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03704480
Sponsor's protocol ID
IMMUNO-BIL D18-1 PRODIGE 57
Acronym
IMMUNO-BIL
Status last verified
Jul 2025
First submitted
28 Sep 2018
Last updated
23 Jul 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Boileve A, Hilmi M, Gougis P, Cohen R, Rousseau B, Blanc JF, Ben Abdelghani M, Castanie H, Dahan L, Tougeron D, Metges JP, Tournigand C, Garcia-Larnicol ML, Vernerey D, Turpin A, Neuzillet C. Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Eur J Cancer. 2021 Jan;143:55-63. doi: 10.1016/j.ejca.2020.10.027. Epub 2020 Dec 3.

    PubMed 33279854

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Durvalumab and Tremelimumab in people with Advanced Biliary Tract Carcinoma, run by GERCOR - Multidisciplinary Oncology Cooperative Group at 28 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 23 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (OS) in amended Arm A (time frame: At 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03704480, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2025.

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