Phase 2 Evaluation of Neoadjuvant Gemcitabine, Cisplatin, Durvalumab, and Tremelimumab in Intrahepatic Cholangiocarcinoma
- Trial ID
- 2024-515660-31-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to demonstrate the **safety** and feasibility of neoadjuvant Gemcitabine plus Cisplatin combined with Durvalumab and Tremelimumab in patients with intrahepatic cholangiocarcinoma, as indicated by achieving an R0/R1 resection rate greater than 65%. This is clinically relevant as it aims to improve surgical outcomes and potentially increase the resectability of tumors, which is crucial for enhancing patient prognosis in this aggressive cancer type.
Secondary objectives include evaluating the following: - Pathological response rates - Impact on radiological resectability - Radiological response - Safety and toxicity - 90-day perioperative morbidity and mortality - Quality of life
Participants
The clinical trial involves participants diagnosed with **intrahepatic cholangiocarcinoma**. The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have a life expectancy of at least 12 weeks and a body weight greater than 30 kg. They are required to have adequate normal organ and marrow function. The trial does not include a vulnerable population. Participants must not have received prior systemic or local therapy, nor have undergone partial or complete tumor resection for intrahepatic cholangiocarcinoma. The sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the technical resectability of the primary tumor and the availability of tumor tissue for translational research. The trial population was selected based on these criteria, ensuring participants have not been previously treated for the condition and have at least one lesion qualifying as a RECIST 1.1 target lesion at baseline.
Plans and Procedures
The clinical trial is designed to evaluate the safety and feasibility of a **neoadjuvant** treatment regimen consisting of **gemcitabine hydrochloride**, **cisplatin**, **durvalumab**, and **tremelimumab** in patients with **intrahepatic cholangiocarcinoma**. This is a Phase II, randomized, double-blind, controlled trial with an estimated duration extending until March 31, 2026. The primary objective is to achieve an R0/R1 resection rate greater than 65%. Secondary endpoints include pathological response rates, radiological resectability and response, safety and toxicity, 90-day perioperative morbidity, mortality, and quality of life (QoL).
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as life expectancy, body weight, organ function, and performance status. The trial will include multiple follow-up visits to monitor treatment response and safety, with the end-of-study visit marking the conclusion of participant involvement. The expected length of participant involvement is contingent upon the treatment regimen, with a maximum treatment period of up to six months for certain drugs. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study protocols.
The trial will employ a rigorous methodology to ensure the integrity of the data collected. Participants will be randomly assigned to treatment groups, and both participants and investigators will be blinded to the treatment assignments to minimize bias. The trial will be conducted in accordance with ethical guidelines and regulatory requirements, ensuring that all participants provide informed consent prior to enrollment. The study aims to contribute valuable insights into the treatment of intrahepatic cholangiocarcinoma, potentially improving outcomes for patients with this rare and challenging condition.
Treatment
The clinical trial involves the administration of several treatments, including **IMFINZI** (durvalumab), which is a **concentrate for solution for infusion**. This experimental medication is provided at a concentration of 50 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 1500 mg, with a total maximum dose of 4500 mg over a treatment period of up to 3 months. Durvalumab is a protein-based therapeutic agent developed by AstraZeneca AB, and it is utilized in this study to evaluate its efficacy and safety in combination with other treatments.
Another treatment used in the trial is **CISPLATIN**, a chemotherapy drug provided as a **concentrate for solution for infusion**. It is administered through **infusion** with a maximum daily dose of 25 mg/m² and a total maximum dose of 150 mg/m² over a treatment period of up to 6 months. Cisplatin is a chemical-based agent and serves as a standard-of-care therapy in the study, contributing to the evaluation of the combined treatment regimen's effectiveness.
**GEMCITABINE HYDROCHLORIDE** is also included in the trial as a chemotherapy drug. It is supplied as a **powder for solution for infusion** and administered via **infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 6000 mg/m² over a treatment period of up to 6 months. This chemical-based agent is used in conjunction with other treatments to assess the overall therapeutic impact on intrahepatic cholangiocarcinoma.
The trial further incorporates **IMJUDO** (tremelimumab), which is a **concentrate for solution for infusion**. This medication is administered through **intravenous infusion** at a concentration of 20 mg/mL. The maximum daily and total dose is 300 mg, with a treatment period limited to 1 month. Tremelimumab, like durvalumab, is a protein-based therapeutic developed by AstraZeneca AB, and it is evaluated for its potential to enhance the treatment outcomes when used in combination with other agents in the study.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the R0/R1-resection rates, which will evaluate the success of surgical tumor removal in patients with intrahepatic cholangiocarcinoma. Secondary endpoints include pathological response rates, radiological resectability and response, safety and toxicity, 90-day perioperative morbidity, mortality, and quality of life (QoL). These endpoints will provide a comprehensive evaluation of the treatment's impact on the disease and patient well-being.
The trial involves the administration of a combination of **Gemcitabine**, **Cisplatin**, **Durvalumab**, and **Tremelimumab**. The efficacy parameters will be measured at various timepoints throughout the study, although specific timepoints are not detailed in the provided data. The assessment of these parameters will likely involve imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate tumor response, as well as histopathological examination to determine pathological response rates. Safety and toxicity will be monitored to ensure patient safety throughout the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must have a life expectancy of at least 12 weeks
- Ability of patient to understand nature, importance and individual consequences of clinical trial
- Sufficient language skills to comprehend verbal and written information and 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
- Age >18 years
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- At least 1 lesion, not previously treated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to treatment start
- Histologically confirmed diagnosis of iCCA and available tumor tissue for translational research
- Technical resectability of the primary tumor
- No prior systemic or local therapy and no prior partial or complete tumor resection for iCCA
- Body weight >30 kg
- Adequate normal organ and marrow function as defined in the protocol
- Women post-menopausal for more than two years can participate in the trial. Women with childbearing potential can only participate, if they are surgically sterile or a negative pregnancy test (serum) is available within 7 days before trial and they are willing to either be totally sexually abstinent OR practice at least one highly effective and medically accepted contraception method during trial (see chapter 7.1). They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and continue to use it throughout the total duration of the drug treatment and the drug washout period (180 days after the last dose of durvalumab + tremelimumab and Gemcitabine/Cisplatin combination therapy)
- Men must agree to remain abstinent or use contraceptive measures, and agree to refrain from donating sperm, as defined: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 180 days after the last dose of study treatment to avoid exposing the embryo. Vasectomised males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study
Exclusion Criteria
- Concurrent enrolment in another clinical study, unless it is an observational (non- interventional) clinical study prior to inclusion and during the study
- Medical or psychological conditions that would jeopardize an adequate and orderly completion of the trial
- 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 antigen4 (anti-CTLA- 4) antibody, therapeutic cancer vaccines
- Any other concurrent antineoplastic treatment including chemotherapy, biologic or hormonal therapy or irradiation
- Any unresolved toxicity NCI CTCAE (V5.0) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Major surgical procedures, open biopsy or significant traumatic injury within 4 weeks prior to treatment start (minor procedures within 1 week)
- Prior radiation therapy within 14 days prior to study entry
- History of allogenic organ transplantation
- History of autologous/allogenic bone marrow transplant
- 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.]). Few exceptions to this criterion are defined in the protocol
- Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure (New York Heart Association Class III or IV), 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 or could compromise protocol objectives in the opinion of the Investigator and/or Sponsor
- Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to enrollment. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") within 3 months of enrollment
- Have Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male), or history of congenital long QT syndrome. Any ECG abnormality that in the opinion of the Investigator would preclude safe participation in the study; patients with pacemakers where QTc is not a reliable measure will require an evaluation by a cardiologist to exclude co-existing cardiac conditions which would prohibit safe participation in the study
- Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites
- History of another primary malignancy (for exceptions see protocol)
- History of leptomeningeal carcinomatosis
- History of active primary immunodeficiency
- Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy
- 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). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. Few expeptions to this rule are described in the protocol
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP
- Female patients who are pregnant or breastfeeding
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Infiltration of any adjacent organs or structures by CT or MRI, indicating an unresectable situation
- 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
- 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
- Preexisting hearing impairment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 27 Jun 2023 | 31 |
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 |
|---|---|---|---|---|---|---|
GEMCITABINE HYDROCHLORIDE | Test | — | INFUSION | 1000 | 6 | SUB02324MIG |
CISPLATIN | Test | — | INFUSION | 25 | 6 | SUB07483MIG |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1500 | 3 | PRD6651398 |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 300 | 1 | PRD10239824 |