Efficacy and Safety of Radioembolization with Cisplatin, Gemcitabine, and Durvalumab in Unresectable Intrahepatic Cholangiocarcinoma
- Trial ID
- 2024-516498-57-00
- Protocol
- PM-CARE
- Sponsor
- Ospedale San Raffaele S.r.l.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy**, defined as the overall response rate, of radioembolization (TARE) followed by a combination of cisplatin and gemcitabine plus durvalumab in patients with liver-predominant unresectable intrahepatic cholangiocarcinoma. Additionally, the study aims to evaluate the safety of this therapeutic scheme. This is clinically relevant as it explores a novel treatment approach for a challenging condition, potentially improving patient outcomes.
Secondary objectives include:
- Evaluating median progression-free survival.
- Conducting an interim assessment of the efficacy of the treatment regimen.
- Describing tumor biological aspects using mRECIST criteria on imaging time points and determining the overall response rate according to mRECIST and RECIST 1.1 criteria at three and six months.
- Investigating the relationship between tumor circulating markers and tumor tissue-based markers.
- Assessing quantitative non-invasive imaging and radiomics-based parameters.
- Analyzing genetic markers in tissue and biological substrates.
- Evaluating tumor mutational burden and the immunological landscape in responders and non-responders to treatment at given time points and among time points, as well as quantitative imaging-based parameters in responders and non-responders.
Participants
The clinical trial involves **patients** diagnosed with unresectable liver predominant intrahepatic cholangiocarcinoma. The study population includes both male and female participants aged between 18 and 80 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have adequate renal and hepatic function, as well as preserved liver function, and must not have been previously treated with systemic or surgical therapies for their condition. The trial population was selected based on specific inclusion criteria, including a life expectancy of at least 12 weeks and no technical contraindications to transarterial radioembolization (TARE). The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **single-arm**, multicenter phase II study to evaluate the efficacy and safety of a novel therapeutic scheme in patients with unresectable liver predominant intrahepatic **cholangiocarcinoma**. The trial involves the administration of radioembolization followed by a combination of **cisplatin**, **gemcitabine**, and **durvalumab**. The primary objective is to assess the overall response rate according to mRECIST criteria at six months, alongside evaluating safety through adverse events, laboratory findings, and vital signs. The trial is expected to commence recruitment on April 2, 2024, and conclude by November 30, 2025, with an estimated participant involvement duration of six months.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as adequate renal and hepatic function, ECOG Performance Score of 0 or 1, and a life expectancy of at least 12 weeks. Following successful screening, participants will receive treatment and attend scheduled follow-up visits to monitor treatment response and safety. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the protocol, or if the investigator deems it in their best interest.
The trial employs a rigorous methodology to ensure the reliability of results, with serial imaging and blood sampling conducted at specified intervals to evaluate treatment efficacy and safety. The study's design does not include a control group, as it is a single-arm trial, and all participants will receive the investigational treatment. The trial's endpoints include both primary and secondary measures, with secondary endpoints focusing on additional imaging criteria and biological sample analyses. The study is not classified as low intervention, given the investigational nature of the therapeutic scheme and the comprehensive monitoring required throughout the trial duration.
Treatment
The clinical trial involves the administration of **Cisplatin**, marketed as Cisplatino Accord Healthcare Italia 1 mg/ml, which is a **solution for infusion**. This chemotherapeutic agent is administered intravenously at a dosage of 25 mg/m², with a maximum total dose of 300 mg/m² over a treatment period of up to 6 months. The pharmaceutical form is a concentrate for solution for infusion, and it is produced by Accord Healthcare S.L.U. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring for potential adverse effects.
**Durvalumab**, marketed as IMFINZI 50 mg/mL, is another investigational product used in this trial. It is a monoclonal antibody, specifically an immunoglobulin G1 Kappa (IgG1), and is administered as a concentrate for solution for infusion. The maximum daily dose is 1500 mg, with a total dose not exceeding 9000 mg over a 6-month period. This agent is produced by AstraZeneca AB and is administered intravenously. The dosing schedule is structured to maximize the immunotherapeutic potential of durvalumab in combination with other agents in the study.
The trial also includes **Gemcitabine**, marketed as Gemcitabina Accord 100 mg/ml, which is an antimetabolite and broad-spectrum deoxycytidine analogue with antineoplastic activity. It is administered as a solution for infusion, with a dosage of 1000 mg/m² and a maximum total dose of 12000 mg/m² over a 6-month period. This product is also manufactured by Accord Healthcare S.L.U. and is delivered via intravenous infusion. The administration of gemcitabine is carefully scheduled to complement the effects of cisplatin and durvalumab, enhancing the overall therapeutic regimen.
Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure adherence to the treatment protocol. The combination of these agents aims to assess the efficacy and safety of the therapeutic scheme in patients with liver-predominant unresectable intrahepatic cholangiocarcinoma. The trial does not include any non-experimental treatments such as placebo or standard-of-care therapy, focusing solely on the investigational combination of cisplatin, gemcitabine, and durvalumab.
Efficacy
The efficacy of the therapeutic scheme in the clinical trial will be assessed primarily by evaluating the **overall response rate (ORR)** according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria on imaging at six months. This primary endpoint will provide a measure of the treatment's effectiveness in patients with liver predominant unresectable intrahepatic cholangiocarcinoma. Secondary endpoints include the ORR according to mRECIST and RECIST 1.1 criteria at three months for interim analysis, and the ORR according to RECIST 1.1 criteria at six months. Additionally, serial blood sampling for cytokine profiling and biopsy prior to and following treatment will be conducted. Serial imaging at specified time points will also be utilized to monitor treatment response.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- Patients with liver predominant intrahepatic cholangiocarcinoma with intermediate/high rate of early recurrence calculated according to https://k-sahara.shinyapps.io/Veryearly-recurrence/
- Patients aged >/= 18 at time of study entry
- Body weight >30kg
- Suspicion or biopsy confirmed diagnosis of ICC or mixed tumor histotype (CCA- HCC), not previously treated with systemic or surgical therapies, including not previously enrolled in another clinical study with an investigational product
- Preserved liver function as defined as: Child Pugh Class A; Model for End Stage Liver Disease Score (MELD) <10; Future Liver Remnant (FLR) uptake function ≥2.7%/min/m2 on technetium-99m mebrofenin hepatobiliary scintigraphy and FLR volume> 30% of total functional liver volume for a normal liver, or> 40% of total functional liver volume if the liver has been damaged by chronic liver disease, cholestasis, steatohepatitis or diabetes
- No technical contraindications to TARE as confirmed by pre-procedural angiographic and scintigraphy
- DNA tests for hepatitis B virus (HBV) and RNA tests for hepatitis C virus (HCV) negative at Screening
- Adequate heart and lung function
- ECOG Performance Score 0 or 1
- Adequate renal and hepatic function as indicated by: serum creatinine <2x upper limit of normal and estimated glomerular filtration rate (eGFR) ≥30ml/min or 1.73m2; measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976*) or by 24-hour urine collection for determination of creatinine clearance**; Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal (ULN) and total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (this will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician)
- Hemoglobin ≥9 g/dL, platelet count ≥75,000/mm3, absolute neutrophil count (ANC) ≥ 1.0 x 109 /L
- Patient is 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
- Must have a life expectancy of at least 12 weeks
Exclusion Criteria
- History of severe cardiovascular disease such as a previous stroke, coronary artery disease requiring surgery, or unresolved arrhythmias within the past 6 months
- Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
- 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
- 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 IP and of low potential risk for recurrence; Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- Evidence of any hematological malignancy
- History of active primary immunodeficiency - Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2) (serum or RNA) - and / or hepatitis B virus surface antigen (HBsAg) positive and/or active Treponema pallidum infection or Mycoplasma (active tuberculosis infection); Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti‑HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
- Alcohol abuse in the 2 months prior to study or other substance abuse in the 6 months prior to the study
- Pregnant or breastfeeding women or women planning to become pregnant
- Known bleeding diathesis or history of abnormal bleeding or any other known coagulation abnormality that may contraindicate future surgery or biopsies
- Child-Pugh class B or more or evidence of severe portal hypertension at screening or at any time up to and including baseline
- Use of systemic immunosuppressants or steroids (prednisone equivalent> 10 mg/day)
- 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, 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
- Active autoimmune conditions
- Patients weighing <30kg will be excluded from enrollment
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP and up to 90 days after the last dose
- Presence of Hepatopulmonary shunt >20% at diagnostic angiography/99mTC-MAA.
- Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
- Presence of Hepatopulmonary shunt >20% at diagnostic angiography/99mTC-MAA
- History of major gastrointestinal bleeding that required medical intervention within 30 days prior to screening or baseline
- 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
- Known hypersensitivity to tumor specific chemotherapy agents used during the study
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Previous allogeneic bone marrow transplant, kidney or liver transplant, i.e. - history of allogenic organ transplantation
- Active viral, bacterial or fungal infection, clinically relevant for the assessment of suitability
- Current history or evidence of neuropsychiatric diseases, including depression, schizophrenia, bipolar disorder, impaired cognitive function, dementia, or suicidal tendency
- 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]). The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin condition that does not require systemic therapy; Patients without active disease in the last 5 years may be included but only after consultation with the study physician; Patients with celiac disease controlled by diet alone
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 02 Apr 2024 | 28 |
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 |
|---|---|---|---|---|---|---|
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 1500 | 6 | PRD6651398 |
Cisplatino Accord Healthcare Italia 1 mg/ml concentrato per soluzione per infusione | Test | CONCENTRATO PER SOLUZIONE PER INFUSIONE | SOLUTION FOR INFUSION | 25 | 6 | PRD3327489 |
Gemcitabina Accord 100 mg/ml concentrato per soluzione per infusione. | Test | CONCENTRATO PER SOLUZIONE PER INFUSIONE | INTRAVENIOUS INFUSION | 1000 | 6 | PRD3332925 |