Trial document




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  DRKS00003893

Trial Description

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Title

Neoadjuvant chemoradioation for resectable, non-metastasized ductal adenocarcinoma of the pancreas

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Trial Acronym

NEOPA

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Median overall-survival (OS) after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially “curative” R0 resection. To achieve better local control, neoadjuvant chemo-radiation therapy (CRT) has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist. The underlying hypothesis of this trial is that neoadjuvant CRT increases the three-year overall survival by 12% (30% to 42%) compared to patients undergoing upfront surgery for resectable pancreatic cancer. Therefore, two groups will be build, patients allocated to the intervention arm will receive a preoperative chemoration followed by a resection of the tumor. Patients in the control arm will undergo upfront surgery, patients in both arm will receive a postoperative chemotherpy (gemcitabin).
Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial. Circumferential resection margin status, i.e. R0 and R1 rates, respectively, surgical resectability rate, local and distant disease-free and global survival, and first site of tumor recurrence constitute further essential endpoints of the trial.

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Brief Summary in Scientific Language

Median OS after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially “curative” R0 resection. To achieve better local control, neoadjuvant CRT has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist. The underlying hypothesis of this randomized, two-armed, open-label, multicenter, phase III trial is that neoadjuvant CRT increases the three-year overall survival by 12% compared to patients undergoing upfront surgery for resectable pancreatic cancer. A rigorous, standardized technique of histopathologically handling Whipple specimens will be applied at all participating centers. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial.

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Organizational Data

  •   DRKS00003893
  •   2014/01/03
  •   [---]*
  •   yes
  •   Approved
  •   PVN4472, Ethik-Kommission der Ärztekammer Hamburg
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Secondary IDs

  •   2012-003669-17 
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Health Condition or Problem studied

  •   C25.0 -  Malignant neoplasm: Head of pancreas
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Interventions/Observational Groups

  •   Neoadjuvant CRT with weekly Gemcitabine 300mg/m2 for 6 weeks combined with external beam radiotherapy (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions will be followed by classical or pylorus-preserving partial pancreato-duodenectomy (PD) and adjuvant chemotherapy, preferentially using Gemcitabine.
  •   Upfront partial pancreato-duodenectomy followed by adjuvant CTx, preferentially with Gemcitabine
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

Survival time (3-year survival rate)

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Secondary Outcome

1. Histology-proven R0 resection rate based on a standardized histopathological handling of the surgical specimen.
2. Frequency of moderate and severe toxicity events and drop-out rate due to therapy related toxicity (NCI Common Toxicity Criteria v4.0)
3. Resectability rate (Note: includes both R0 and R1 resection status)
4. Rate of unexpected intraoperative irregularities, operative time, blood transfusion requirement, postoperative morbidity rate, especially that of pancreatic fistula, and mortality rate
5. Rate of patients with severe postoperative complications (postop. recovery > 8 weeks) rendering adjuvant treatment worthless
6. Disease progression during neoadjuvant therapy
7. Quality of life analysis (EORTC QLQ C30 questionnaire). After completion of neoadj. RCTx, postoperative, 6, 12 and 18 months after completion of therapy.
8. Median disease-free survival (DFS, local and distant), overall survival (OS) (3-year follow-up)
9. First site of tumor recurrence

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Planned
  •   2014/01/20
  •   410
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

• Histology-proven adenocarcinoma of the pancreatic head/uncinate process with a tumor size greater 2 cm (≥cT2) and/or close contact to the superior mesenteric vessels (≤3 mm in preoperative staging).
• No evidence of metastasis to distant organs (liver, peritoneum, lung, others).
• For determination of resectability, a multi-detector CT (MDCT) with at least 16 rows applying both oral and intravenous contrast media is performed. MDCT-based imaging focuses on the upper abdomen with native, arterial, and parenchyma phase, where the parenchyma phase should include the pelvis. Imaging criteria derived from the recent consensus definition of the Society of Surgical Oncology, the American Society of Clinical Oncology and the American Hepato-Pancreatico-Biliary Association are applied for preoperative assessment of local resectability.
• Potential Resectability: visualizable fat plane around celiac and superior mesenteric arteries, and patent superior mesenteric/portal vein (SMV/PV).
• Borderline Resectability: substantial superior mesenteric/portal vein impingement, tumor abutment on the SMA < 180°, GDA encasement up to the origin of the hepatic artery, or colonic/mesenteric root invasion.
• Karnofsky performance status ≥ 80%
• Serum creatinine level ≤ 3.0 mg/dl
• Serum total bilirubin level ≤ 3.0 mg/dl in the absence of biliary obstruction (In the event of biliary obstruction, patients allocated to the CRT group must undergo interventional endoscopy or percutaneous drainage for biliary decompression. Post-interventionally, bilirubin levels should be ≤ 3.0 mg/dl before patients are subjected to CRT. In control patients undergoing upfront surgery, serum total bilirubin levels ≤ 10.0 mg/dl are tolerated, unless clinical and laboratory signs of severe cholangitis take place. Patients with serum total bilirubin level > 10.0 mg/dl undergo preoperative biliary decompression, preferentially by interventional endoscopy)
• White blood cell count > 3.5 x 109/ml, platelet count > 100 x 109/ml
• Ability to understand and willingness to consent to formal requirements for study participation
• Written informed consent

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Exclusion Criteria

• Age < 18 years
• Neuroendocrine, acinar cancer
• Cancers of the pancreatic body or tail, i.e. lesions left to the SMV
• Recurrent disease
• Infiltration of extrapancreatic organs (except duodenum and transverse colon)
• Persistent cholestasis/cholangitis despite adequate biliary stenting
• Distant metasasis
• High-grade therapyresistant stenotic gastric outlet obstruction, especially in the event of endoscopically evidenced tumor invasion into the gastroduodenal mucosa.
• Tumor specific pre-treatment
• History of gastrointestinal perforation, e.g. perforated colonic diverticulitis, abdominal abscess or intestinal fistula within 6 months prior to potential study participation
• Radiographic evidence of severe portal hypertension/cavernomatous transformation that may, at the discretion of the participating investigators, hamper surgery
• Other concurrent malignancies except for basal cell cancer of the skin and in-situ cervical cancer
• Premalignant hematologic disorders, e.g. myelodysplastic syndrome
• Severe organ dysfunctions (e.g. Liver cirrhosis ≥ Child B; Cardio-pulmonal diseases (NYHA ≥III, arrhythmia Lown III/IV, global respiratory insufficiency); Ascites; Acute pancreatitis; bleeding diathesis, coagulopathy, need for full-dose anticoagulation or INR > 1.5; other severe diseases that might prevent completion of the treatment regimen)
• Chronic infectious diseases, especially immune deficiency syndromes, e.g. HIV infection, active tuberculosis within 12 months prior to potential study participation
• Severe neurologic disorders, e.g. cerebrovascular ischemia
• History of prior deep venous thrombosis or pulmonary embolism
Pregnant or nursing women are ineligible and patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial and for 6 months following the trial
• Serious medical, psychological, familial, sociological or geographical conditions or circumstances potentially hampering compliance with the study protocol and follow-up
• Participation in other clinical trials during the last 6 months before allocation to trial

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Addresses

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    • Universitätsklinikum Hamburg-Eppendorf
    • Martinistr. 52
    • 20246  Hamburg
    • Germany
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    • Universitätsklinikum Hamburg-Eppendorf Klinik für Allgemein-, Viszeral- und Thoraxchirurgie
    • Mr.  Dr. med.  Michael  Tachezy 
    • Martinistrasse 52
    • 20246  Hamburg
    • Germany
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    • Universitätsklinikum Hamburg-Eppendorf Klinik für Allgemein- Viszeral- und Thoraxchirurgie
    • Mr.  Dr. med.  Florian  Gebauer 
    • Martinistrasse 52
    • 20246  Hamburg
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung (BMBF) Dienstsitz Bonn
    • Heinemannstr. 2
    • 53175  Bonn
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.