A Phase IIIb, Single Arm, Open-label, Multicentre Study of Durvalumab in Combination with Chemotherapy for the First Line Treatment for Patients with Advanced Biliary Tract Cancers (TOURMALINE)
- Trial ID
- 2022-502043-35-01
- Protocol
- D4191C00140
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety** of durvalumab when combined with background gemcitabine-based chemotherapy in patients with advanced biliary tract cancers. Evaluating the safety profile is clinically relevant as it helps determine the risk-benefit ratio of this combination therapy, ensuring that the treatment does not pose undue harm to patients.
Secondary objectives include:
- Assessing the efficacy of durvalumab combined with background gemcitabine-based chemotherapy, which is crucial for understanding the therapeutic potential and clinical benefits of the treatment.
- Further assessing the safety and tolerability profile of the combination, providing a comprehensive understanding of the treatment's impact on patient health and quality of life.
- Evaluating disease- and treatment-related symptoms and health-related quality of life (HRQoL), which is important for understanding the overall patient experience and the treatment's effect on daily living.
Participants
The clinical trial involves a total of **140 participants** diagnosed with **Advanced Biliary Tract Cancers**, including cholangiocarcinoma, gallbladder carcinoma, and ampulla of Vater carcinoma. The study population comprises both male and female subjects, aged 18 years and older, with a body weight exceeding 30 kg. Participants are required to have a World Health Organization/Eastern Cooperative Oncology Group performance status of 0 to 2, indicating they are ambulatory and capable of self-care. The trial includes individuals with previously untreated disease, as well as those who have undergone prior curative intent treatment. Participants must have adequate organ and marrow function and a life expectancy of at least 12 weeks. The selection process ensures that participants are capable of providing informed consent and comply with study requirements. Lifestyle considerations such as diet and physical activity are not specified, but participants with hepatitis B virus infection must be on antiviral therapy. The trial population includes a vulnerable population, highlighting the need for careful monitoring and ethical considerations throughout the study.
Plans and Procedures
The clinical trial is designed to evaluate the safety of **durvalumab** in combination with gemcitabine-based chemotherapy for the treatment of patients with advanced biliary tract cancers. This is a Phase IIIb, single-arm, open-label, multicenter study. The trial is expected to commence recruitment on March 1, 2024, and conclude by March 17, 2026. Participants will be involved in the study for a maximum treatment period of 24 months, with the possibility of early termination if adverse events or other conditions necessitate withdrawal.
The trial will include a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, weight, and medical history. Participants must have a histologically confirmed diagnosis of unresectable advanced or metastatic biliary tract cancer and meet specific organ function requirements. Following the screening, participants will receive the study intervention, with regular follow-up visits scheduled to monitor safety and efficacy outcomes. The primary endpoint is the incidence of Grade 3 or 4 adverse events possibly related to the study intervention within six months of initiation. Secondary endpoints include overall survival, objective response rate, progression-free survival, and duration of response.
Study visits will include assessments of vital signs, laboratory tests, and imaging studies to evaluate the response to treatment. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants will be monitored for adverse events, and any serious or treatment-emergent adverse events will be documented. The study will adhere to ethical guidelines, and informed consent will be obtained from all participants prior to any study-related procedures.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Carboplatin** is provided as a 10 mg/mL concentrate for solution for infusion. It is administered via infusion, with a maximum treatment period of 2 weeks. The pharmaceutical form is a solution for infusion, and it is classified as an antineoplastic agent. The product is manufactured by Fresenius Kabi Deutschland GmbH.
**Oxaliplatin** is available as a 5 mg/mL concentrate for solution for infusion, also administered via infusion. The treatment period is limited to 2 weeks. This platinum compound is produced by Accord Healthcare B.V.
**Cisplatin** is supplied as a 1 mg/mL concentrate for solution for infusion, administered through infusion. The maximum treatment period is 2 weeks. It is categorized as a cytostatic agent and is manufactured by Accord Healthcare Ireland Limited.
**Gemcitabine** is provided as a 100 mg/mL concentrate for solution for infusion, administered via infusion. The treatment duration is up to 2 weeks. It is classified as an antineoplastic agent and produced by Accord Healthcare Ireland Limited.
**Infliximab** is available as a 100 mg powder for concentrate for solution for infusion, administered through intravenous infusion. The maximum daily dose is 350 mg, with a total dose of 1050 mg over a 6-week period. It is an immunosuppressive agent manufactured by Pfizer Europe MA EEIG.
**Mycophenolate mofetil** is provided in 250 mg hard capsules for oral use. The maximum daily dose is 2 grams, with a total dose of 168 grams over a 12-week period. It is classified as an immunosuppressive agent and produced by Generis Farmacêutica, S.A.
**Durvalumab** is supplied as a 50 mg/mL concentrate for solution for infusion, administered via intravenous infusion. The maximum daily dose is 1500 mg, with a total dose of 12000 mg over a 24-week period. It is manufactured by AstraZeneca AB and serves as the primary test medication in the trial.
All medications are sourced locally and used in accordance with their marketing authorization. Participant compliance is monitored throughout the trial to ensure adherence to dosing schedules and administration routes.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on the incidence of **PRAE** (possibly related adverse events) Grade 3 or 4, associated with the administration of durvalumab in combination with gemcitabine-based chemotherapy, within six months of initiating durvalumab treatment. This will be evaluated by the investigator to determine the safety profile of the treatment regimen.
Secondary endpoints include overall survival (OS), objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), and duration of treatment (DOT). OS will be measured from the date of the first dose until death from any cause, with specific interest in median OS, OS at 12, 18, and 24 months. ORR will be determined by the proportion of participants achieving a confirmed complete response (CR) or partial response (PR) as per RECIST 1.1 criteria. PFS will be assessed from the first dose until disease progression or death, with measures of interest including median PFS, PFS at 12 and 18 months. DCR will be evaluated by the percentage of participants with a best objective response of CR or PR by Week 24/32 or stable disease (SD) for at least 24/32 weeks. DOR will be calculated from the first documented response to progression or death.
Additional assessments will include the incidence, severity, and nature of treatment-emergent adverse events (AEs), including PRAEs, adverse events of special interest (AESIs), immune-mediated AEs (imAEs), and serious adverse events (SAEs). The study will also monitor laboratory findings, infusion-related reactions (IRRs), and hypersensitivity or anaphylactic reactions. Patient-reported outcomes will be evaluated using the EORTC QLQ-C30 and QLQ-BIL21 questionnaires, focusing on global health status, quality of life, and specific symptoms such as abdominal pain, pruritus, and jaundice. Changes from baseline and best overall responses will be assessed at each post-baseline evaluation.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 years and above legal age per local regulations at the time of screening.
- Histologically confirmed, unresectable advanced or metastatic BTC including cholangiocarcinoma (intrahepatic or extrahepatic), gallbladder carcinoma, and AoV carcinoma
- Participants with previously untreated disease are eligible if presented with unresectable or metastatic BTC at initial diagnosis.
- Prior curative intent treatment (surgery and, if given in the adjuvant setting, chemotherapy and/or radiation) is permitted, regardless of time to recurrence. This includes participants with residual disease after surgery, who received chemotherapy, chemoembolization, or radiotherapy.
- A WHO/ECOG PS of 0 to 2.
- At least one lesion that qualifies as a RECIST 1.1 TL at baseline.
- Participants with HBV infection (as characterised by positive HBsAg and/or anti-HBcAb with detectable HBV DNA, as per local laboratory standards) must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (as per local laboratory standards) prior to enrolment. Participants must remain on antiviral therapy for the study duration and for 6 months after the last dose of durvalumab. Participants who test positive for anti-HBc with undetectable HBV DNA (as per local laboratory standards) do not require antiviral therapy prior to enrolment.
- Adequate organ and marrow function, as defined below. − Haemoglobin ≥ 9 g/dL − Absolute neutrophil count ≥ 1.5 × 10*9 /L − Platelet count ≥ 100 × 10*9 /L − Serum bilirubin ≤ 2.0 × ULN; this will not apply to participants with confirmed Gilbert’s syndrome. Any clinically significant biliary obstruction should be resolved before enrolment. − ALT and AST ≤ 2.5 × ULN. For participants with hepatic metastases, ALT and AST ≤ 5 × ULN. − Calculated creatinine clearance > 50 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance. For chemotherapy regimens including carboplatin, oxaliplatin, or gemcitabine as monotherapy, the recommended threshold for calculated creatinine clearance is > 40 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance.
- Must have a life expectancy of at least 12 weeks.
- Body weight of > 30 kg.
- Male or female.
- Negative pregnancy test (serum) for women of childbearing potential.
- Female participants must be one year post-menopausal (amenorrhoeic for 12 months without an alternative medical cause), surgically sterile, or using one highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). Women of childbearing potential must agree to use one highly effective method of birth control (see Appendix H in the protocol for a complete list of highly effective birth control methods) from the time of screening throughout the total duration of the study and up to 90 days after the last dose of durvalumab or up to end of the period specified in the SmPC or package insert of the background gemcitabine-based chemotherapy agents, whichever is longer. − Non-sterilised male partners of a woman of childbearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) throughout this period. Cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, as well as the rhythm and withdrawal methods are not acceptable methods of birth control.
- Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or on their chosen method of birth control from the time of screening throughout the total duration of the study and up to 90 days after the last dose of durvalumab or up to end of the period specified in the SmPC or package insert of the background gemcitabine-based chemotherapy agents, whichever is longer, to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. − Female partners (of childbearing potential) of male participants must also use a highly effective method of contraception throughout this period.
- Participant is capable of giving signed informed consent as described in Appendix A, Section A3 in the protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Written informed consent from the participant has been obtained prior to any study-related procedures.
- Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of sample for optional genomics initiative research that supports Genomic Initiative.
Exclusion Criteria
- As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations), history of uncontrolled or symptomatic cardiac disease, and history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis, or Wegener syndrome [granulomatosis with polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: − Participants with vitiligo or alopecia. − Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. − Any chronic skin condition that does not require systemic therapy. − Participants without an active disease in the last 5 years may be included. − Participants with celiac disease controlled by diet alone. − Participants with ≥ Grade 2 lymphopenia will be evaluated on a case-by-case basis.
- History of another primary malignancy, except for malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy, or adequately treated carcinoma in situ without evidence of disease.
- History of leptomeningeal carcinomatosis.
- History of active primary immunodeficiency.
- Known to have tested positive for HIV (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- Participants co-infected with HBV (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA, as per local laboratory standards) and HCV (presence of anti-HCV antibodies), or coinfected with HBV and HDV (presence of anti-HDV antibodies).
- Persistent toxicities (CTCAE Grade > 1) caused by previous anticancer therapy; alopecia and vitiligo are excluded toxicities. − Participants with Grade ≥ 1 neuropathy will be evaluated on a case-by-case basis. − Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab in the opinion of the Investigator may be included.
- Central nervous system metastases requiring treatment or history of spinal cord compression (including asymptomatic and adequately treated disease). Participants with suspected brain metastases at screening should have an MRI (preferred) or CT scan, each preferably with IV contrast of the brain prior to study entry.
- Known allergy or hypersensitivity to any of the study intervention or any of the study intervention excipients.
- Any concurrent chemotherapy, other than the one allowed in the study, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions (eg, hormone replacement therapy) is acceptable.
- Palliative radiotherapy with a limited field of radiation within 2 weeks of the first dose of study intervention, or radiotherapy with a wide field of radiation or radiotherapy affecting more than 30% of the bone marrow within 4 weeks before the first dose of study intervention. Prior locoregional therapy, such as radioembolization, is allowed as long as done more than 2 weeks prior.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention (see Appendix J in the protocol). Enrolled participants should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of IP.
- Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of IP. Minor surgery of isolated lesions for palliative intent is acceptable if performed more than 14 days prior to the first dose of IP.
- Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: − Intranasal, inhaled, or topical steroids or local steroid injections (eg, 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 (eg, CT scan premedication).
- Receipt of the last dose of anticancer therapy (chemotherapy, targeted therapy, biologic therapy, or mAbs) within 28 days prior to the first dose of study intervention or 5 half-lives of the anticancer therapy whichever is longer.
- Participation in another clinical study with a study intervention administered in the last 3 months.
- Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study.
- Prior randomisation or study intervention in a previous durvalumab clinical study, regardless of study intervention arm assignment.
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to use effective birth control from the time of screening throughout the total duration of the study and up to 90 days after the last dose of durvalumab or up to end of the period specified in the SmPC or package insert of the background gemcitabine-based chemotherapy agents, whichever is longer.
- Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Mar 2024 | 19 |
 Germany | Not Recruiting | 01 Mar 2024 | 12 |
 Italy | Not Recruiting | 01 Mar 2024 | 13 |
 Spain | Not Recruiting | 01 Mar 2024 | 32 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Inflectra 100 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 350 | 6 | PRD6483369 |
Cisplatin 1 mg/ml Concentrate for Solution for Infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 0 | 2 | PRD1951589 |
Oxaliplatine Accord 5 mg/ml concentraat voor oplossing voor infusie | Other | CONCENTRAAT VOOR OPLOSSING VOOR INFUSIE | INFUSION | 0 | 2 | PRD1785468 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1500 | 24 | PRD6651398 |
Micofenolato de mofetil Generis 250 mg Cápsulas | Other | CÁPSULAS | ORAL USE | 2 | 12 | PRD1816611 |
Carboplatin 10 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 0 | 2 | PRD7277959 |
Gemcitabine 100 mg/ml Concentrate for Solution for Infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 0 | 2 | PRD1980125 |