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.

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.

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