Phase II Evaluation of Durvalumab and Tremelimumab with Y-90 SIRT in Advanced Intrahepatic Biliary Tract Cancer
- Trial ID
- 2023-508314-42-00
- Protocol
- IMMUWHY
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **anti-tumor activity** of durvalumab or durvalumab combined with tremelimumab, administered following standard-of-care selective internal radiation therapy (SIRT) in patients with unresectable advanced stage intrahepatic biliary tract cancer. This is measured by the objective response rate (ORR), which is clinically significant as it provides insight into the effectiveness of the treatment in reducing tumor size or extent.
Secondary objectives include:
- Assessing the safety of the combined treatment in the two treatment arms, which is crucial for determining the risk-benefit profile of the therapies.
- Evaluating the efficacy of durvalumab or durvalumab and tremelimumab, as measured by duration of response (DoR), progression-free survival (PFS), and overall survival (OS). These metrics are important for understanding the long-term benefits and potential survival advantages of the treatment.
- Exploratory objective: Assessing predictive biomarkers for ORR, DoR, PFS, and OS in tumor tissue and blood samples, which may help in identifying patients who are more likely to benefit from the treatment.
Participants
The clinical trial involves participants diagnosed with **advanced stage intrahepatic biliary tract cancer (BTC)**. The study population includes both male and female subjects, with an age range of 18 years and older. Participants are required to have a histologically documented diagnosis of locally-advanced or limited metastasized intrahepatic BTC that is not amenable to curative treatment. The trial population was selected based on specific inclusion criteria, such as adequate hepatic function, a life expectancy of at least 12 weeks, and a performance status of 1 or less on the ECOG scale. Participants must also have adequate bone marrow and renal function. The trial includes individuals with prior chemotherapy and/or immunotherapy, provided they meet certain conditions. Lifestyle considerations, such as diet and physical activity, are not specified. The sponsor has not provided information on the total number of participants. The study includes a vulnerable population, and both genders are represented. Key inclusion criteria emphasize the necessity for participants to have at least one measurable primary site of disease and to be candidates for standard-of-care Y-90 SIRT therapy, as determined by the investigator and tumor board consultation.
Plans and Procedures
The clinical trial is designed to evaluate the **anti-tumor activity** of **durvalumab** or a combination of **durvalumab** and **tremelimumab** in patients with advanced stage intrahepatic biliary tract cancer (BTC) who are scheduled to receive Y-90 SIRT therapy as part of their standard care. This is a phase II, randomized, double-blind, controlled trial. The trial aims to measure the objective response rate (ORR) as the primary endpoint, with secondary endpoints including safety, duration of response, progression-free survival, overall survival, and exploratory predictive biomarkers for ORR, DoR, PFS, and OS. The trial is expected to run from November 2020 to December 2026, with an estimated participant involvement of up to 72 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate hepatic function, life expectancy of at least 12 weeks, and a performance status of ≤1 on the ECOG scale. Following the screening, participants will be randomized to receive either **durvalumab** alone or in combination with **tremelimumab**. The treatment will be administered via **intravenous infusion**. Regular follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. Additionally, any participant who does not comply with the study protocol or develops a condition that contraindicates continued participation may also be removed from the trial. The trial is conducted in accordance with ethical guidelines and requires fully informed written consent from all participants prior to any protocol-related procedures.
Treatment
The clinical trial involves the administration of **IMJUDO**, a 20 mg/mL concentrate for solution for infusion, containing the active substance **tremelimumab**. This pharmaceutical form is a sterile concentrate intended for intravenous infusion. The maximum daily dose is 300 mg, with a total dose not exceeding 300 mg over the treatment period. The administration is conducted via intravenous infusion, and the treatment duration is limited to a single day. Tremelimumab is a protein-based therapeutic agent, classified under the ATC code L01FX20, and is produced by AstraZeneca AB. Participant compliance with the dosing schedule is monitored throughout the trial.
Additionally, the trial includes the administration of **IMFINZI**, a 50 mg/mL concentrate for solution for infusion, containing the active substance **durvalumab**. This medication is also a sterile concentrate for intravenous infusion. The maximum daily dose is 1500 mg, with a cumulative dose limit of 27000 mg over a 72-week treatment period. Durvalumab, like tremelimumab, is a protein-based therapeutic agent and is classified under the ATC code L01XC28. It is also manufactured by AstraZeneca AB. The administration of durvalumab is conducted via intravenous infusion, and participant adherence to the dosing regimen is closely monitored.
The trial does not involve any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to evaluate the anti-tumor activity of durvalumab or the combination of durvalumab and tremelimumab following standard-of-care Y-90 SIRT therapy in patients with unresectable intrahepatic biliary tract cancer. The study aims to measure the objective response rate (ORR) as the primary endpoint.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as measured by RECIST 1.1 criteria. This endpoint will evaluate the anti-tumor activity of the investigational treatments, durvalumab or durvalumab combined with tremelimumab, administered following standard-of-care Y-90 SIRT therapy in patients with unresectable intrahepatic biliary tract cancer. The ORR will provide a quantifiable measure of the proportion of patients experiencing a predefined reduction in tumor size.
Secondary efficacy endpoints include the **Duration of Response (DoR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**. These parameters will offer additional insights into the long-term benefits of the treatment regimen. Safety, as indicated by the rate of adverse events, will also be monitored as a secondary endpoint. Exploratory analyses will investigate predictive biomarkers for ORR, DoR, PFS, and OS, potentially identifying factors that correlate with treatment efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
- Age ≥ 18 years.
- Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as • Tumor being confined to the liver or • In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent*AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation. *Limited extent is defined in this protocol as presence of o EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm) o OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm). o Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4) • Tumor tissue (block or at least 4 slides) is available for translational research.
- Patients with prior chemotherapy and/or immunotherapy can be enrolled if ONE of the following cirteria is met: • Capecitabin or gemcitabine+cisplatin in the adjuvant setting • Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting • Stable disease after 3 months of gemcitabine+cisplatin treatment • Experienced progressive disease under durvalumab+ gemcitabine+cisplatin in first line treatment • Experienced progressive disease under pembrolizumab+ gemcitabine+cisplatin in first line treatment
- Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT. Contraindications against SIRT would be o hepatic tumor load > 50% o Any Gastrointestinal deposition that cannot be corrected via angiographic techniques o irreversibly elevated serum bilirubin o renal insufficiency o increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs o gastrointestinal ulceration o hepatic dysfunction o biliary complications o portal hypertension o vascular injury and lymphopenia.
- Performance status (PS) ≤ 1 (ECOG scale).
- Body weight >30 kg
- At least one measurable primary site of disease as defined by RECIST 1.1 criteria.
- Adequate bone marrow and renal function including the following: o Hemoglobin ≥ 9.0 g/dL; o absolute neutrophil count ≥ 1.5 x 103/L; o platelets ≥100x 109/L; o Creatinine ≤ 1.5 x upper normal limit. o Calculated creatinine clearance ≥40 mL/min as determined by the Cockcroft-Gault equation
- Adequate hepatic function (with stenting for any obstruction, if required) including the following: o Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); o AST (SGOT) / ALT (SGPT) ≤ 2.5x institutional ULN (NOTE: if liver metastases are present AST / ALT must be ≤ 5x institutional ULN; o prothrombin time 60%; o albumin 30 g/L.
- Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
- 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: o 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). o 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).
- The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
- Must have a life expectancy of at least 12 weeks.
- If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria: - Patients with HBV or HCV infection should be monitored for viral levels during study participation. - Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines. Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment. - HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.
Exclusion Criteria
- 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.
- Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
- Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines, apart from durvalumab and pembrolizumab as PD-L1 inhibitor in first line therapy.
- Presence of peritoneal carcinomatosis or brain metastases
- 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 o Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab and tremelimumab may be included only after consultation with the Coordinating Investigator.
- Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
- Prior radiotherapy treatment before the first dose of any study drug
- Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
- 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], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis]. The following are exceptions to this criterion: o Patients with vitiligo or alopecia o Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement o Any chronic skin condition that does not require systemic therapy o Patients without active disease in the last 5 years may be included but only after consultation with the study physician
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, 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.
- History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2 pneumonitis.
- History of another primary malignancy except for: o Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of IP and of low potential risk for recurrence o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease o Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry.
- History of active primary immunodeficiency
- History of allogenic organ transplantation.
- Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: o Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection) o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent o Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab.
- Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
- Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study.
- Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
- Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 25 Nov 2020 | 40 |
 Spain | Not Recruiting | 25 Nov 2020 | 10 |
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 |
|---|---|---|---|---|---|---|
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INTRAVENOUS INFUSION | 300 | 1 | PRD10239824 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1500 | 72 | PRD6651398 |