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Neoadjuvant Treatment in Resectable Pancreatic Cancer (NEOPA)

This study is currently recruiting participants.
See Contacts and Locations
Verified January 2015 by Universitätsklinikum Hamburg-Eppendorf
Sponsor:
Collaborators:
University of Schleswig-Holstein
Hannover Medical School
St. Josef Hospital Bochum
University of Jena
SRH Wald-Klinikum Gera GmbH
Klinikum Darmstadt
Saarland University
Heidelberg University
Staedtisches Klinikum Karlsruhe
University Hospital Freiburg
University Hospital Regensburg
Technische Universität München
Klinikum Augsburg
Klinikum Stuttgart
Ludwig-Maximilians - University of Munich
University of Rostock
Information provided by (Responsible Party):
Universitätsklinikum Hamburg-Eppendorf
ClinicalTrials.gov Identifier:
NCT01900327
First received: June 27, 2013
Last updated: January 30, 2015
Last verified: January 2015
  Purpose
Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma

Condition Intervention Phase
Pancreatic Cancer Radiation: External Beam Radiation Drug: Gemcitabine neoadjuvant Procedure: Surgery Drug: Gemcitabine adjuvant Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma

Resource links provided by NLM:


Further study details as provided by Universitätsklinikum Hamburg-Eppendorf:

Primary Outcome Measures:
  • 3-Year Survival Rate [ Time Frame: 3 years after last patient in ]
    Primary outcome measure is the efficacy of neoadjuvant CRT in improving 3-year survival probability from 30% in the control arm undergoing upfront surgery without neoadjuvant CRT to 42% (relative increase of 40%) in the study arm undergoing CRT. The underlying guess of a 30% 3-year survival probability in the control group derives from an assumed median overall survival (MOS) of 20.7 months which corresponds with a MOS of 17.9 months to 23.6 months reported in several randomized trials.


Secondary Outcome Measures:
  • R0 Resection rate [ Time Frame: 3 days ]
    Histology-proven R0 resection rate based on a standardized histopathological handling of the surgical specimen.

  • Frequency of Toxicity Events [ Time Frame: three years ]
    Frequency of moderate and severe toxicity events and drop-out rate due to therapy related toxicity (NCI Common Toxicity Criteria v2.0)

  • Resectability rate [ Time Frame: one day ]
    Resectability rate

  • Rate of intraoperative irregularities [ Time Frame: one day ]
    Rate of unexpected intraoperative irregularities, operative time, blood transfusion requirement, postoperative morbidity rate, especially that of pancreatic fistula, and mortality rate

  • Postoperative Complications [ Time Frame: three months ]
    Rate of patients with severe postoperative complications (postoperative recovery > 8 weeks) rendering adjuvant treatment worthless

  • Disease progression during neoadjuvant therapy [ Time Frame: three months ]
    Rate of patients with disease progression during neoadjuvant therapy (only applicable in treatment arm)

  • Quality of life [ Time Frame: three years ]
    Quality of life analysis (EORTC QLQ C30 questionnaire). Assessment of QLQ after completion of neoadjuvant RCTx, after surgery (before hospital discharge) and 6, 12 and 18 months after completion of treatment

  • Disease-free Survival [ Time Frame: three years ]
    Median disease-free survival (DFS, local and distant), overall survival (OS)

  • First site of tumor recurrence [ Time Frame: two years ]
    First site of tumor recurrence as determined by abdominal computed tomography during follow-up study visits


Estimated Enrollment: 410
Study Start Date: February 2014
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: February 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: neoadj. Treatment
Neoadjuvant CRT with weekly Gemcitabine neoadjuvant 300mg/m2 for 6 weeks combined with external beam radiation (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 (CTx), preferentially using Gemcitabine adjuvant (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle).
Radiation: External Beam Radiation
Neoadjuvant CRT with external beam radiation (EBRT) delivering a total dose of 50.4 Gy over 28 days in 1.8 Gy fractions.
Other Names:
  • External Beam Radiation Therapy
  • EBRT
Drug: Gemcitabine neoadjuvant
weekly Gemcitabine 300mg/m2 for 6 weeks neoadjuvant
Other Names:
  • Gemcitabin
  • Gemzar
Procedure: Surgery
Upfront pancreato-duodenectomy
Other Name: Tumor resection
Drug: Gemcitabine adjuvant
Postoperative adjuvant Chemotherapy preferentially using Gemcitabine (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle. Administered in both arms, experimental AND active comparator
Other Names:
  • Gemcitabin
  • Gemzar
  • 2',2'-Difluordesoxycytidin
Active Comparator: Upfront Surgery
Upfront PD followed by adjuvant CTx, preferentially with Gemcitabine adjuvant (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle).
Procedure: Surgery
Upfront pancreato-duodenectomy
Other Name: Tumor resection
Drug: Gemcitabine adjuvant
Postoperative adjuvant Chemotherapy preferentially using Gemcitabine (1000 mg/m2 6 cycles at day 1, 8, 15 of each 28-day cycle. Administered in both arms, experimental AND active comparator
Other Names:
  • Gemcitabin
  • Gemzar
  • 2',2'-Difluordesoxycytidin

Detailed Description:
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 randomized, two-armed, open-label, multicenter, phase III 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. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial, taking into regard an expected drop out rate of 7% and allocated either to receive neoadjuvant CRT prior to surgery or to undergo surgery alone. 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.
  Eligibility

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

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 [1] 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

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
  • 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
  • History of 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01900327

Contacts
Contact: Jakob R Izbicki, MD, FACS +4940741052401 neopa@uke.de

Locations
Germany
University Freiburg Recruiting
Freiburg, Baden-Württemberg, Germany, 79106
Contact: Ulrich Hopt, MD       ulrich.hopt@uniklinik-freiburg.de   
Sub-Investigator: Uwe Wittel, MD         
Principal Investigator: Urlich Hopt, MD         
Heidelberg University Not yet recruiting
Heidelberg, Baden-Württemberg, Germany, 69120
Contact: Markus Büchler, MD       Markus.Buechler@med.uni-heidelberg.de   
Principal Investigator: Markus Büchler, MD         
Sub-Investigator: Lutz Schneider, MD         
Technische Universität München Not yet recruiting
München, Bayern, Germany, 81675
Contact: Jörg , kleef@tum.de         
Principal Investigator: Jörg Kleef, MD         
Sub-Investigator: Andre Mhaljevic, MD         
University Regensburg Suspended
Regensburg, Bayern, Germany, 93053
Klinikum Augsburg Active, not recruiting
Augsburg, Bayer, Germany, 86156
Klinikum Darmstadt Active, not recruiting
Darmstadt, Hessen, Germany, 64283
University of Rostock Not yet recruiting
Rostock, Mecklenburg-Vorpommern, Germany, 18057
Contact: Ernst Klar, MD       ernst.klar@med.uni-rostock.de   
Principal Investigator: Ernst Klar, MD         
Hannover Medical School Not yet recruiting
Hannover, Niedersachsen, Germany, 30625
Contact: Jürgen Klempnauer, MD       klempnauer.juergen@mh-hannover.de   
Contact: Steffan Jackobs, MD       Jackobs.Steffan@mh-hannover.de   
Principal Investigator: Jürgen Klempnauer, MD         
Sub-Investigator: Steffen Jackobs, MD         
St. Joseph Hospital Bochum Active, not recruiting
Bochum, Nordrhein-Westfalen, Germany, 44791
Saarland University Active, not recruiting
Homburg, Saarland, Germany, 66421
University of Schleswig-Holstein Kiel Active, not recruiting
Kiel, Schleswig-Holstein, Germany, 24105
University of Schleswig-Holstein Lübeck Active, not recruiting
Lübeck, Schleswig-Holstein, Germany, 23538
Klinikum Gera Active, not recruiting
Gera, Thüringen, Germany, 07548
University of Jena Active, not recruiting
Jena, Thüringen, Germany, 07747
University Medical Center Hamburg-Eppendorf Recruiting
Hamburg, Germany, 20246
Contact: Florian Gebauer, MD    +4940741050152    fgebauer@uke.de   
Principal Investigator: Jakob R Izbicki, MD, FACS         
Sub-Investigator: Florian Gebauer, MD         
Sub-Investigator: Michael Tachezy, MD         
Sub-Investigator: Maximilian Bockhorn, MD         
Sub-Investigator: Oliver Mann, MD         
Klinikum Karlsruhe Active, not recruiting
Karlsruhe, Germany, 76133
Sponsors and Collaborators
Universitätsklinikum Hamburg-Eppendorf
University of Schleswig-Holstein
Hannover Medical School
St. Josef Hospital Bochum
University of Jena
SRH Wald-Klinikum Gera GmbH
Klinikum Darmstadt
Saarland University
Heidelberg University
Staedtisches Klinikum Karlsruhe
University Hospital Freiburg
University Hospital Regensburg
Technische Universität München
Klinikum Augsburg
Klinikum Stuttgart
Ludwig-Maximilians - University of Munich
University of Rostock
Investigators
Principal Investigator: Jakob R Izbicki, MD, FACS Universitätsklinikum Hamburg-Eppendorf
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Universitätsklinikum Hamburg-Eppendorf
ClinicalTrials.gov Identifier: NCT01900327     History of Changes
Other Study ID Numbers: NEOPA
Study First Received: June 27, 2013
Last Updated: January 30, 2015

Keywords provided by Universitätsklinikum Hamburg-Eppendorf:
pancreatic cancer
surgery
chemoradiation
neoadjuvant treatment
overall survival

Additional relevant MeSH terms:
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 26, 2017