Neoadjuvant Chemotherapy With Gemcitabine Plus Cisplatin Followed by Radical Liver Resection Versus Immediate Radical Liver Resection Alone With or Without Adjuvant Chemotherapy in Incidentally Detected Gallbladder Carcinoma After Simple Cholecystectomy or in Front of Radical Resection of BTC

Neoadjuvant Chemotherapy With Gemcitabine Plus Cisplatin Followed by Radical Liver Resection Versus Immediate Radical Liver Resection Alone With or Without Adjuvant Chemotherapy in Incidentally Detected Gallbladder Carcinoma After Simple Cholecystectomy or in Front of Radical Resection of BTC (ICC/ECC) - A Phase III Study of the German Registry of Incidental Gallbladder Carcinoma Platform (GR) - The AIO/ CALGP/ ACO- GAIN-Trial -

Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC)

The aim of the study is to investigate whether induction chemotherapy followed by radical re-resection (and - if possible - postoperative chemotherapy) in incidental gallbladder carcinoma (IGBC) or in front radical resection in biliary tract cancer (BTC) (intrahepatic cholangiocarcinoma (ICC)/ extrahepatic cholangiocarcinoma (ECC)) prolongs overall survival without impaired quality of life compared to immediate radical surgery alone with or without adjuvant chemotherapy (investigator's choice) in patients with IGBC, or BTC (ICC/ECC). One of the most important secondary objectives is to raise awareness for the necessity of a radical second surgery as well as to improve the adherence to the treatment guidelines in IGBC. Further secondary objectives are safety and tolerability of the treatment as well as quality of life.

Inclusion criteria

1. Incidental gallbladder carcinoma (IGBC), gallbladder carcinoma (GBC) () or Biliary tract cancer (BTC) (intrahepatic, hilar or distal Cholangiocarcinoma (CCA)) scheduled for complete resection (mixed tumor entities with hepatocellular carcinoma are excluded).

2. No prior partial or complete tumor resection for BTC (intrahepatic, hilar or distal CCA), and for IGBC/GBC prior Cholecystectomy is allowed.

3. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI, indicating an unresectable situation.

4. ECOG performance status of 0, 1, or 2.

5. Estimated life expectancy > 3 months.

6. Female and male patients1 ≥18 years.

7. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

8. No previous or preceding cytotoxic or targeted therapy for BTC or IGBC/GBC.

9. No previous malignancy within two years or concomitant malignancy, except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer

10. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last three months, significant arrhythmia).

11. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.

12. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial.

13. A) Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 7 months after the last study treatment.

    A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (has not had ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

    B) Males must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm, as defined below:

    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 6 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.

14. No pregnancy or lactation.

15. Adequate hematologic function: ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 9 g/dl or ≥ 5.59 mmol/L; prior transfusions for patients with low hemoglobin are allowed

16. Adequate liver function as measured by serum transaminases (AST and ALT) ≤ 5 x ULN and bilirubin ≤ 3 x ULN.

17. Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN, a calculated glomerular filtration rate ≥ 30 mL/min.

18. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to randomization.

19. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy (patients on long-term antibiotics are eligible provided signs of active infection have been resolved).

20. No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days or five half-lives (whichever is longer) prior to randomization.

21. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause Please note that after randomization for patients in Arm A the histological confirmation of BTC or GBC must be performed before administering chemotherapy. For IGBC histological confirmation should already have been performed.

For Arm B patients the histological confirmation can be performed after surgery with material from the surgery.

Exclusion criteria

1. Known hypersensitivity against gemcitabine or cisplatin

2. Other known contraindications to gemcitabine or cisplatin

3. Clinically significant valvular defect

4. Past or current history of other malignancies not curatively treated and without evidence of disease for more than two years, except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer

5. Locally unresectable tumor or metastatic disease:

   • Radiological evidence suggesting inability to resect with curative intent whilst maintaining adequate vascular inflow and outflow, and sufficient future liver remnant
   • Radiological evidence of direct invasion into adjacent organs
   • Radiological evidence of extrahepatic metastatic disease

6. Other severe internal disease or acute infection

7. Chronic inflammatory bowel disease

8. Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents.

9. 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") during 3 months prior to randomization.

10. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.

11. On-treatment participation in another clinical study 30 days or five half-lives (whichever is longer) prior to inclusion and during the study

12. Pregnant or breast feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment.

13. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)

14. Any other concurrent antineoplastic treatment including irradiation