Efficacy of Gemcitabine Hydrochloride and Cisplatin Versus Standard Care in Post-Resection Cholangiocarcinoma and Muscle-Invasive Gallbladder Carcinoma
- Trial ID
- 2024-517340-61-00
- Protocol
- ACTICCA-1
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **gemcitabine** and **cisplatin** compared with the standard of care in patients with biliary tract cancer (BTC) after complete resection, specifically in terms of disease-free survival (DFS). This is clinically relevant as it aims to determine whether the combination of these chemotherapeutic agents can improve DFS compared to the current standard treatments, which include observation alone in stage 1 and capecitabine and observation in stage 2. Improved DFS could potentially lead to better long-term outcomes for patients who have undergone curative intent resection for cholangiocarcinoma or muscle invasive gallbladder carcinoma.
Secondary objectives include assessing the safety and tolerability of the treatment, as well as relapse-free survival (RFS) and overall survival (OS). Additionally, the study will evaluate the quality of life, the function of biliodigestive anastomoses, and the quantity and quality of information patients have gained after informed consent. The involvement of patients in the decision-making process, known as shared decision making, will also be assessed. These secondary objectives are important for understanding the broader impact of the treatment on patient well-being and healthcare outcomes.
Participants
The clinical trial involves a total of **277 participants** who have undergone curative intent resection for **cholangiocarcinoma** (intrahepatic, hilar, or distal) or muscle invasive gallbladder carcinoma, without evidence of metastatic disease. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on specific eligibility criteria, including a histologically confirmed diagnosis of non-metastatic adenocarcinoma of the biliary tract following radical surgical therapy with macroscopically complete resection. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include adequate hematologic, liver, and renal function, as well as the absence of severe or uncontrolled cardiovascular disease, psychiatric disorders, or serious underlying medical conditions that could impair participation. Additionally, participants must not have received prior chemotherapy for biliary tract cancer and must not have any concurrent malignancies, except for those with a high survival rate, such as non-melanomatous skin cancer or adequately treated in situ cervical cancer. Fertile women and procreative men are required to use effective contraception, and pregnant or lactating women are excluded from the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **gemcitabine hydrochloride** and **cisplatin** compared to the standard of care in patients who have undergone curative intent resection for **cholangiocarcinoma** or muscle invasive gallbladder carcinoma. This is a randomized, double-blind, controlled trial with an estimated end date of December 31, 2025. The trial involves a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as histologically confirmed adenocarcinoma of the biliary tract, adequate organ function, and no prior chemotherapy for biliary tract cancer. Participants will be randomly assigned to receive either the investigational treatment or the standard of care, which includes observation alone or in combination with **capecitabine**.
The trial duration for each participant is expected to be up to 24 months, with treatment periods for **gemcitabine hydrochloride** and **cisplatin** lasting up to 24 and 18 weeks, respectively. Follow-up visits will be conducted to monitor disease-free survival (DFS), recurrence-free survival (RFS), overall survival (OS), and other secondary endpoints such as quality of life and safety. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent.
Participants will be required to attend regular follow-up visits to assess the primary endpoint of DFS and secondary endpoints, including DFS rate at 24 months, safety, and tolerability of the adjuvant chemotherapy. The trial aims to provide comprehensive data on the efficacy and safety of the investigational regimen in improving outcomes for patients with these specific types of cancer. The study is conducted in accordance with ethical guidelines, and all participants must provide written informed consent prior to enrollment.
Treatment
The clinical trial involves the administration of **Capecitabine**, a chemotherapeutic agent, in the form of a **film-coated tablet**. The active substance, capecitabine, is of chemical origin. The medication is administered orally with a maximum daily dose of 2500 mg/m² and a total maximum dose of 280,000 mg/m² over a treatment period of up to 24 months. The role of capecitabine in the trial is as a comparator treatment, and it is not a pediatric formulation.
**Cisplatin** is another chemotherapeutic agent used in this trial, provided as a **solution for infusion**. The active substance, cisplatin, is also of chemical origin. It is administered intravenously with a maximum daily dose of 25 mg/m² and a total maximum dose of 400 mg/m² over a treatment period of up to 18 months. Cisplatin serves as a test treatment in the study and is not formulated for pediatric use.
**Gemcitabine Hydrochloride** is included in the trial as a **solution for infusion**. The active substance, gemcitabine hydrochloride, is chemically derived. This medication is administered intravenously with a maximum daily dose of 1000 mg/m² and a total maximum dose of 16,000 mg/m² over a treatment period of up to 24 months. Gemcitabine hydrochloride is utilized as a test treatment in the trial and is not intended for pediatric patients.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of gemcitabine and cisplatin compared to standard-of-care treatments in patients with cholangiocarcinoma and muscle-invasive gallbladder carcinoma following complete resection.
Efficacy
The efficacy of the treatment in this clinical trial will be assessed primarily through the evaluation of **Disease-Free Survival (DFS)**. This endpoint measures the length of time after treatment during which the patient remains free from any signs or symptoms of the cancer. Secondary endpoints include the **Disease-Free Survival Rate at 24 months (DFSR@24)**, **Recurrence-Free Survival (RFS)**, **Overall Survival (OS)**, and the **Safety and Tolerability of Adjuvant Chemotherapy**. Additional secondary endpoints involve assessments of **Quality of Life (QoL)**, the function of **biliodigestive anastomosis**, the rate and severity of **biliary tract infections**, patterns of **disease recurrence**, and **locoregional control**.
The trial will compare the efficacy of gemcitabine and cisplatin against the standard of care, which includes observation alone in stage 1 and capecitabine and observation in stage 2, in patients with biliary tract cancer (BTC) following complete resection. The efficacy parameters will be collected and analyzed at various time points throughout the study, with a particular focus on the 24-month mark for DFSR. The study is designed to provide a comprehensive evaluation of the treatment's impact on patient outcomes, with a focus on both survival metrics and quality of life indicators.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Eligibility criteria for enrolment phase 1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) scheduled for radical surgical therapy 2. Written informed consent 3. No prior chemotherapy for biliary tract cancer 4. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer 5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 9. No pregnancy or lactation
- Eligibility criteria for treatment phase (before randomization) All enrolled patients will postoperatively be assessed for eligibility for the treatment phase. Additionally patients not previously enrolled into the trial for whatever reason (e.g. incidental finding during surgery) will be evaluated for eligibility. 1. Histologically confirmed non metastatic adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) after radical surgical therapy with macroscopically complete resection (mixed tumor entities (HCC/CCA) are excluded) including resection of adjacent lymph nodes (according to appendix H) 2. Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled start of chemotherapy 3. ECOG 0-1 4. Age ≥18 years 5. Adequate hematologic function: ANC 1.5 x 109/L, platelets 100 x109/L, hemoglobin 9 g/dl or 5.59 mmol/L 6. Adequate liver function as measured by serum transaminases (AST and ALT) £5 x ULN and bilirubin £3 x ULN 7. Adequate renal function, i.e. serum creatinine £1.5 x ULN, glomerular filtration rate ≥ 50 ml/min (determination of GFR according to local institutional standards, e.g. MDRD, (Appendix E)) 8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy 9. No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization 10. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause (Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be exceeded)
- Criteria for initial study enrolment 11. Written informed consent 12. No prior chemotherapy for biliary tract cancer cancer 14. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 15. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 16. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 17. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 18. No pregnancy or lactation 13. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical
Exclusion Criteria
- Eligibility criteria for enrolment phase 1. Suspicion of or histologically/cytologically confirmed adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) scheduled for radical surgical therapy 2. Written informed consent 3. No prior chemotherapy for biliary tract cancer 4. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer 5. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 6. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 7. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 8. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 9. No pregnancy or lactation
- Eligibility criteria for treatment phase (before randomization) All enrolled patients will postoperatively be assessed for eligibility for the treatment phase. Additionally patients not previously enrolled into the trial for whatever reason (e.g. incidental finding during surgery) will be evaluated for eligibility. 1. Histologically confirmed non metastatic adenocarcinoma of biliary tract (intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive gallbladder carcinoma) after radical surgical therapy with macroscopically complete resection (mixed tumor entities (HCC/CCA) are excluded) including resection of adjacent lymph nodes (according to appendix H) 2. Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled start of chemotherapy 3. ECOG 0-1 4. Age ≥18 years 5. Adequate hematologic function: ANC 1.5 x 109/L, platelets 100 x109/L, hemoglobin 9 g/dl or 5.59 mmol/L 6. Adequate liver function as measured by serum transaminases (AST and ALT) £5 x ULN and bilirubin £3 x ULN 7. Adequate renal function, i.e. serum creatinine £1.5 x ULN, glomerular filtration rate ≥ 50 ml/min (determination of GFR according to local institutional standards, e.g. MDRD, (Appendix E)) 8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy 9. No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization 10. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause (Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be exceeded)
- Criteria for initial study enrolment 11. Written informed consent 12. No prior chemotherapy for biliary tract cancer 13. No previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer 14. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia) 15. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent 16. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 17. Fertile women (< 1 year after last menstruation) and procreative men willing and able to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) 18. No pregnancy or lactation
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 02 Jan 2014 | 35 |
 Germany | Not Recruiting | 02 Jan 2014 | 335 |
 Italy | Not Recruiting | 02 Jan 2014 | 31 |
 The Netherlands | Not Recruiting | 02 Jan 2014 | — |
| Netherlands | — | — | 172 |
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 |
|---|---|---|---|---|---|---|
CAPECITABINE | Comparator | — | ORAL USE | 2500 | 24 | SUB12474MIG |
GEMCITABINE HYDROCHLORIDE | Test | — | INTRAVENOUS | 1000 | 24 | SUB02324MIG |
CISPLATIN | Test | — | INTRAVENOUS | 25 | 18 | SUB07483MIG |