Adjuvant Chemotherapy With Gemcitabine and Cisplatin Compared to Standard of Care After Curative Intent Resection of Biliary Tract Cancer

Study Overview
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Brief Summary
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This is a multicenter, prospective, randomized, controlled phase III trial designed to assess the clinical performance of gemcitabine with cisplatin and observation vs. standard of care (observation alone in stage 1 and capecitabine and observation in stage 2) in patients after curative intent resection of BTC.

Detailed Description
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The ACTICCA-1 investigator initiated trial is funded by the Deutsche Krebshilfe (grant number 70110215, 70112047). With respect to data obtained in the ABC-02 trial, the combination of cisplatin and gemcitabine for 24 weeks as investigational treatment was selected. Based on adjuvant trials in pancreatic cancer (e.g. ESPAC IV) with a comparable postoperative recovery time, inclusion of patients within a maximum interval of 16 weeks between surgery and start of CTx was chosen. Gemcitabine and cisplatin has a relevantly higher cumulative dose of gemcitabine 18 vs. 12 applications and may thus be of increased efficacy compared to the gemcitabine/oxaliplatin regimen applied in the PRODIGE 12 trial. Based on the data of the BILCAP trial showing an improvement in median overall survival for capecitabine compared to observation alone presented at the annual meeting of the American Society of Clinical Oncology on June 4th 2017 in Chicago by the British BILCAP trial group, capecitabine has evolved as the new standard of care after curative intent resection of biliary tract cancer. Based on these data the comparative efficacy of gemcitabine/cisplatin and capecitabine had to be established. Therefore, the ACTICCA trial was amended to compare gemcitabine and cisplatin to the newly established standard regimen in the adjuvant setting capecitabine, aiming for superiority of the combination regimen vs. the oral monotherapy This was based on the BILCAP protocol, applying the similar dosing, assessments and dose modifications as in BILCAP, including dose calculation and patient diary. As data of recent trials like the French PRODIGE 12/ACCORD 18 trial have clearly shown that in terms of efficacy of an adjuvant chemotherapy there is no difference between cholangiocarcinoma and gall bladder carcinoma, these two subtypes are pooled and location was added as an stratification factor. Randomization will be 1:1 with adjuvant CTx for 24 weeks and imaging every 12 weeks in the experimental arm and standard of care (capecitabine) and observation in the control arm. The primary endpoint is DFS and secondary endpoints include recurrence free survival, OS, safety and tolerability of adjuvant CTx, quality of life, and patterns of disease recurrence.

Official Title
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Adjuvant Chemotherapy With Gemcitabine and Cisplatin Compared to Standard of Care After Curative Intent Resection of Cholangiocarcinoma and Muscle Invasive Gall Bladder Carcinoma (ACTICCA-1 Trial)

Conditions
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Cholangiocarcinoma, Gall Bladder Carcinoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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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. Histologically confirmed 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) Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled start of chemotherapy ECOG 0-1 Age ≥18 years Adequate hematologic function Adequate liver function Adequate renal function No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days prior to randomization 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 Written informed consent No prior chemotherapy for cholangiocarcinoma No previous malignancy within 3 years or concomitant malignancy, except: non-melanomatous skin cancer or adequately treated in situ cervical cancer 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) Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial 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) No pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine plus Cisplatin<br>Chemotherapy will be administered on days 1 and 8 every 3 weeks, Cisplatin (25 mg per square meter of body-surface area) and Gemcitabine (1000 mg per square meter) for 24 weeks (8 cycles) and Observation | Drug: Gemcitabine<br>* Gemcitabine 1000mg/m2<br>Drug: Cisplatin<br>* Cisplatin 25mg/m2<br>|
| Active Comparator: Capecitabine<br>Capecitabine will be administered from day 1 to 14 every 3 weeks (1250 mg per square meter of body-surface area, twice daily) for 24 weeks (8 cycles) and Observation | Drug: Capecitabine<br>* Capecitabine 1250mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) | DFS | Disease free survival rate at 24 months (DFSR@24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival rate at 24 months (DFSR@24) | DSFR | 24 months | 
| Recurrence free survival | RFS | 24 months | 
| Overall survival | OS | 84 months | 
| Safety and tolerability (assessed by the rate of patients with adverse events according to NCI CTC AE v4.03) |  | 24 months | 
| Quality of life | QOL | 48 months | 
| Function of biliodigestive anastomosis (in terms of surgical revision, requirement for PTCD) |  | 48 months | 
| Rate and severity of biliary tract infections |  | 48 months | 
| Patterns of disease recurrence |  | 48 months | 
| locoregional control (assessed by the rate of patients with hepatic or locoregional recurrence) |  | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adjuvant chemotherapy, cholangiocarcinoma, muscle invasive gall bladder carcinoma, translational research, multidisciplinary, AIO, DGAV, DGVS