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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 (GAIN)

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ClinicalTrials.gov Identifier: NCT03673072
Recruitment Status : Not yet recruiting
First Posted : September 17, 2018
Last Update Posted : February 27, 2019
Sponsor:
Collaborator:
German Research Foundation
Information provided by (Responsible Party):
Krankenhaus Nordwest

Brief Summary:
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)

Condition or disease Intervention/treatment Phase
Incidental Gallbladder Carcinoma Biliary Tract Cancer Drug: Gemcitabine Drug: Cisplatin Procedure: Oncologically radical margin-free (R0) resection Drug: Adjuvant chemotherapy Phase 3

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 -
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : November 2024
Estimated Study Completion Date : November 2024


Arm Intervention/treatment
Experimental: Arm A (gemcitabine plus cisplatin)
Patients assigned to arm A will receive treatment with gemcitabine plus cisplatin. Chemotherapy will be administered for 3 cycles preoperatively (neoadjuvant part) and for 3 cycles postoperatively (adjuvant part).
Drug: Gemcitabine
Gemcitabine (1000 mg/m2) in 250-500 ml 0.9% saline every three weeks on days 1 and 8 intravenously

Drug: Cisplatin
Cisplatin (25 mg/m2) every three weeks on days 1 and 8 intravenously, in 1000 ml 0.9% saline with KCl 20 mmol and MgSO4 8 mmol during the one hour cisplatin infusion followed by 500 ml 0.9% saline over 30 minutes prior to gemcitabine; with adequate pre- and posthydration

Procedure: Oncologically radical margin-free (R0) resection
Oncologically radical margin-free (R0) resection

Active Comparator: Arm B (standard postoperative management)
Patients assigned to arm B will receive surgery directly, without receiving perioperative chemotherapy (Standard of Care / SOC). After surgery, adjuvant chemotherapy can be administered by investigator's choice.
Procedure: Oncologically radical margin-free (R0) resection
Oncologically radical margin-free (R0) resection

Drug: Adjuvant chemotherapy
Can be selected by Investigator's Choice




Primary Outcome Measures :
  1. Primary efficacy endpoint is overall survival (OS) [ Time Frame: up to 6 years follow-up ]

Secondary Outcome Measures :
  1. Quality of life (EORTC QLQ-C30) [ Time Frame: every 3 weeks until EOT andt then every 3 months up to 6 years of follow-up ]

    "European Organisation for the Research and Treatment of Cancer" Quality of Life Questionnaire Core 30. The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients.

    The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items.

    Each of the multi-item scales includes a different set of items - no item occurs in more than one scale.

    All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

    Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.


  2. PFS (Progression free surviva) rates at 3 and 5 years [ Time Frame: at 3 and 5 years after randomization ]
  3. OS (overall survival) rates at 3 and 5 years [ Time Frame: at 3 and 5 years after randomization ]
  4. Progression free survival (PFS) [ Time Frame: up to 6 years after randomization ]
  5. R0- resection rate [ Time Frame: 2 weeks after surgery (Arm A: 14 weeks after randomization; Arm B: 2 weeks after randomization) ]
  6. Toxicity, graded using CTC adverse events criteria version CTCAE V 5.0 [ Time Frame: up to 6 years after randomization ]
  7. Number of patients with any serious perioperative morbidity or mortality [ Time Frame: up to 30 and 90 days after surgery ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically/cytologically confirmed incidental gallbladder carcinoma (IGBC) (T2-3 after Cholecystectomy) 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), for IGBC (T2-3) 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.
  9. No previous malignancy within five years or concomitant malignancy, except non-melanomatous skin cancer or adequately treated in situ cervical 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 3 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 ULN, glomerular filtration rate ≥ 60 mL/min determined with the MDRD formula.
  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

Exclusion Criteria:

  1. Known hypersensitivity against gemcitabine or cisplatin
  2. Other known contraindications to gemcitabine or cisplatin
  3. Unresolved biliary tract obstruction
  4. 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.
  5. Clinically significant valvular defect
  6. Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
  7. 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
  8. Other severe internal disease or acute infection
  9. Chronic inflammatory bowel disease
  10. 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.
  11. 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.
  12. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.
  13. On-treatment participation in another clinical study 30 days or five half-lives (whichever is longer) prior to inclusion and during the study
  14. Pregnant or breast feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment.
  15. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
  16. Any other concurrent antineoplastic treatment including irradiation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03673072


Contacts
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Contact: Thorsten O Goetze, PD Dr. +49 69 7601-4187 goetze.thorsten@khnw.de
Contact: Salah-Eddin Al-Batran, Prof. Dr. +49 69 7601-4420 albatran.salah@khnw.de

Sponsors and Collaborators
Krankenhaus Nordwest
German Research Foundation

Additional Information:
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Responsible Party: Krankenhaus Nordwest
ClinicalTrials.gov Identifier: NCT03673072     History of Changes
Other Study ID Numbers: GAIN/GEM/CIS
2017-004444-38 ( EudraCT Number )
AIO-HEP-0118/ass ( Other Identifier: AIO )
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD will be shared

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Biliary Tract Neoplasms
Gallbladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Biliary Tract Diseases
Digestive System Diseases
Gallbladder Diseases
Cisplatin
Gemcitabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs