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Neoadjuvant Treatment in Resectable Pancreatic Cancer (NEOPA)

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ClinicalTrials.gov Identifier: NCT01900327
Recruitment Status : Terminated (Recruitment failure)
First Posted : July 16, 2013
Last Update Posted : May 11, 2018
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

Tracking Information
First Submitted Date  ICMJE June 27, 2013
First Posted Date  ICMJE July 16, 2013
Last Update Posted Date May 11, 2018
Study Start Date  ICMJE February 2014
Actual Primary Completion Date November 22, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2013)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01900327 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2013)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Treatment in Resectable Pancreatic Cancer
Official Title  ICMJE Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma
Brief Summary Sequential Neoadjuvant Chemoradiotherapy (CRT) Followed by Curative Surgery vs. Primary Surgery Alone for Resectable, Non-metastasized Pancreatic Adenocarcinoma
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.
Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreatic Cancer
Intervention  ICMJE
  • 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
Study Arms
  • 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).
    Interventions:
    • Radiation: External Beam Radiation
    • Drug: Gemcitabine neoadjuvant
    • Procedure: Surgery
    • Drug: Gemcitabine adjuvant
  • 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).
    Interventions:
    • Procedure: Surgery
    • Drug: Gemcitabine adjuvant
Publications * Tachezy M, Gebauer F, Petersen C, Arnold D, Trepel M, Wegscheider K, Schafhausen P, Bockhorn M, Izbicki JR, Yekebas E. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA- a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer. 2014 Jun 7;14:411. doi: 10.1186/1471-2407-14-411.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 4, 2018)
32
Original Estimated Enrollment  ICMJE
 (submitted: July 11, 2013)
410
Actual Study Completion Date July 2017
Actual Primary Completion Date November 22, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01900327
Other Study ID Numbers  ICMJE NEOPA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Universitätsklinikum Hamburg-Eppendorf
Study Sponsor  ICMJE Universitätsklinikum Hamburg-Eppendorf
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Jakob R Izbicki, MD, FACS Universitätsklinikum Hamburg-Eppendorf
PRS Account Universitätsklinikum Hamburg-Eppendorf
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP