Background
Evidence
Rationale for the trial
Methods and design
Study objectives
Primary objective
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Disease free survival (DFS) rate at 18 months post randomization (DFS rate improvement in one arm of at least ≥55%)
Secondary objectives
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To assess the effect of neoadjuvant nab-paclitaxel/gemcitabine on tumor response rate (RECIST 1.1), histological tumor regression and R0 resection rate
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Effects of perioperative or adjuvant nab-paclitaxel/gemcitabine on 3-years DFS and OS
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Safety
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Pre- and postoperative morbidity and mortality
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Toxicity assessment
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Disease progression rate under neoadjuvant nab-paclitaxel/gemcitabine
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R0 and R1 resection rates
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Correlation of tumor regression and R0 resection rate in the perioperative study arm
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Overall survival (OS)
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First site of tumor recurrence
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Health related quality of life (EORTC QLQ-PAN26, QLQ-C30 and HADS-D questionnaires)
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Correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays)
Patient selection and randomization
Inclusion criteria:
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• Histologically or cytologically proven clearly resectable ductal adenocarcinoma of the pancreas (PDAC) ≤ cT3 with no prior tumor specific treatment. (After consolidation with the coordinating investigator a cytological determination is possible in exceptional cases.) | |
• No evidence of metastases to distant organs (e.g. liver, peritoneum, lung). | |
• ECOG performance status 0 or 1 | |
• Creatinine clearance ≥30 ml/min | |
• Serum total bilirubin level ≤ 2.5 x ULN | |
• ALT and AST ≤ 2.5 x ULN | |
• In case of biliary obstruction, biliary decompression is required. Post-interventional bilirubin levels must be ≤2.5 x ULN | |
• White blood cell count ≥3.5 × 106/ml, neutrophil granulocytes count ≥1,5 × 106/ml, platelet count ≥100 × 106/ml | |
• Signed informed consent incl. Participation in translational research | |
• Age ≥ 18 years and < 75 years | |
Main exclusion criteria
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• Borderline resectable PDAC by radiologic criteria, papillary cancer on neuroendocrine Cancer | |
• Radiographic evidence of severe portal hypertension/cavernous transformation | |
• Chronic infectious diseases, immune deficiency syndromes | |
• Premalignant hematologic disorders, e.g. myelodysplastic syndrome | |
• Disability to understand and sign written informed consent document | |
• Past or current history of malignancies except for the indication under this study and curatively treated: | |
▪ Basal and squamous cell carcinoma of the skin | |
▪ In-situ carcinoma of the cervix | |
▪ Other malignant disease without recurrence after at least 5 years of follow-up | |
• Clinically significant cardiovascular disease (incl. Myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment | |
• Clinically relevant or history of interstitial lung disease, e.g. non-infectious pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan or chest x-ray. | |
• Pre-existing neuropathy > grade 1 (NCI CTCAE) | |
• Pregnancy or breastfeeding women. |
Staging assessments (Additional file 2)
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Completed medical history and physical examination
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12 lead ECG/echocardiography
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Contrast enhanced multislice CT of the abdomen/abdominal MRI and chest x-ray/thoracic CT, Ultrasound elasticity imaging of the tumor (optional)
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Hematological tests, Clinical chemistry
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Tumor Marker (Serum): Ca 19–9, CEA
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Signed written informed consent.
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PDAC diagnosis: Core biopsies of the tumor can be obtained via endoscopic ultrasound for histological or cytological assessment. Alternatively tissue samples can be obtained via laparoscopic surgery
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EORTC QLQ-PAN26, QLQ-C30 and HADS-D questionnaire
Treatment
Arm A (perioperative arm)
Arm B (adjuvant arm)
Surgery
Follow-up
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Physical examination including: weight, WHO/ECOG performance status
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EORTC QLQ-PAN26, QLQ-C30 and HADS-D questionnaire
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Abdominal CT/MRI and chest x-ray routinely every three months for 3 years, then abdominal ultrasound every 3 months (if suspicious for relapse: CT/MRI) and abdominal CT/MRI and chest x-ray every 6 months, as an alternative to chest -ray, thoracic CT can be performed at the discretion of the center (recommended)
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Additional Clinical tumor assessments, if appropriate
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Tumor marker (serum): Ca 19–9, CEA
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Eventual second / further line treatment
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Survival status
Sample size calculation and statistical analysis
Quality of life assessment
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At baseline, within 7 days prior to randomization
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Prior CT-scan after 2 cycles of chemotherapy (Arm A)
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The day before surgery (or prior surgery within 3 days)
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After surgery within 4 weeks (week 3–4) prior CT-scan
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Before the beginning of each cycle of systemic therapy,
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At end of treatment visit about 4 weeks (+/− 7 days) after the last application dose of the study drugs
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During the follow up, every 3 months
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Quality of life assessment should be performed even when chemotherapy cannot be given at the beginning of a cycle e.g. due to toxicity reasons.