Prospective Randomized Multicenter Phase II Trial to Investigate Intensified Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer
Overview
- Phase
- Phase 2
- Intervention
- Gem/nab-Pac
- Conditions
- Ductal Adenocarcinoma of the Pancreas
- Sponsor
- AIO-Studien-gGmbH
- Enrollment
- 168
- Locations
- 1
- Primary Endpoint
- Conversion Rate
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The aim ot the study is to investigate the efficacy and safety of two new intensified chemotherapy regimens (gemcitabine (Gem)/nab- paclitaxel (PAC), FOLFIRINOX) as neoadjuvant chemotherapy protocol in locally advanced, non-metastatic pancreatic cancer (LAPC) and consecutive conversion of the tumor to resectability.
Detailed Description
This is a prospective open randomized multicenter phase II trial with two arms. Patients suffering from histologically confirmed LAPC (and assessed as unresectable or borderline resectable according to National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines "pancreatic adenocarcinoma" version 1.2013) without metastases will receive two different neoadjuvant treatment regimens: First all patients receive two cycles Gem/nab-PAC (duration of each cycle 28 days) as neoadjuvant chemotherapy in equal measure and a first restaging is performed after these two cycles based on imaging criteria. If there is no progression according to Response evaluation criteria in solid tumors (RECIST 1.1) criteria at the first restaging, the patients are randomized in a 1:1 relation to: Two further cycles Gem/nab-PAC (duration of each cycle 28 days). or Four further cycles FOLFIRINOX (duration of each cycle 14 days). After the neoadjuvant chemotherapy a 2nd restaging is performed based on imaging criteria. All patients without progression at this restaging or at an earlier time point undergo obligatory exploratory laparotomy irrespective of imaging criteria to assess resectability. If they are evaluated as converted to resectable during this exploratory laparotomy, pancreas resection in curative intent will be performed. All patients with successful R0 or R1 pancreatic resection will receive three further cycles adjuvant chemotherapy with Gem/nab-PAC. Adjuvant chemotherapy will start within 4 to 8 weeks after pancreatic resection surgery. Further treatment of patients with PD after 1st or 2nd restaging as well as patients with unresectable status based on exploratory laparotomy is under the discretion of the local investigators (e.g. second-line chemotherapy in case of distant relapse or local radiochemotherapy in case of local progression or definitive irresectability). All patients are followed up for local recurrence, progression and survival until death or for at least one year after last application of study drugs whichever is sooner. The translational research conducts exploratory analyses for potential biomarkers of possible prognostic or predictive value for efficacy of neoadjuvant chemotherapy in LAPC; including analyses of circulating tumor cells, molecular pathways of pancreatic adenocarcinoma including SPARC expression.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult patients ≥ 18 years and ≤ 75 years of age
- •Histologic or cytologic proven ductal adenocarcinoma of the pancreas (histologic confirmation of diagnosis is preferred)
- •No distant metastases
- •De novo, treatment-naïve unresectable or borderline resectable LAPC; evaluation of unresectable and borderline resectable status according to NCCN- Clinical Practice Guidelines in Oncology "pancreatic adenocarcinoma" version 1.
- •Applicable criterion/criteria have to be indicated.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Total bilirubin ≤ 2 mg/dL. Patients with a biliary stent may be included provided that bilirubin level after stent insertion decreased to ≤ 2 mg/dL and there is no cholangitis.
- •Adequate renal, hepatic and bone marrow function, defined as
- •Serum creatinine ≤ 1.25 x Upper limit of normal (ULN)
- •Calculated creatinine clearance ≥ 60 mL/min according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
Exclusion Criteria
- •Evidence of distant metastases. In case of radiological suspicion of peritoneal carcinomatosis or ascites histological or cytological verification is required e.g. by means of exploratory laparoscopy
- •Local relapse of the pancreatic adenocarcinoma prior treated with surgical resection
- •Any previous treatment of the pancreatic carcinoma (radiotherapy, chemoradiotherapy, chemotherapy, targeted tumor therapy, local ablative therapy)
- •Contraindication for pancreas resection (pancreatic head resection, distal pancreatectomy with splenectomy, or complete pancreatectomy)
- •Larger surgical interventions within 4 weeks before study enrolment and/or diagnostic laparotomy with or without gastroenterostomy and with or without biliodigestive anastomosis within 2 weeks before first application of study treatment. Wound healing must be also completed before first application of study treatment.
- •Known chronic diarrhoea
- •Peripheral polyneuropathy \> grade 1
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency
- •Medical history of interstitial lung disease (ILD) or pulmonary fibrosis
- •Hypersensitivity against any of the study drugs (nab-paclitaxel, gemcitabine, oxaliplatin, irinotecan, 5-fluorouracil, folinic acid), or the ingredients of these drugs
Arms & Interventions
Gem/nab-Pac
2 further cycles Gem/nab-Pac (duration of each cycle 28 days)
Intervention: Gem/nab-Pac
FOLFIFINOX
4 cycles combination therapy with 5-fluorouracil/folinic acid, irinotecan, oxaliplatin (FOLFIFINOX) - duration of each cycle 14 days
Intervention: FOLFIFINOX
Outcomes
Primary Outcomes
Conversion Rate
Time Frame: approx. 10 month
To compare the effect of intensified neoadjuvant chemotherapy on conversion rate to resectability in LAPC.
Secondary Outcomes
- CA 19-9 change(10 month)
- Safety(approx. 22 month)
- objective tumour response rate(approx. 22 month)
- disease control rate (DCR)(approx. 22 month)
- R0 and R1 resections(10 month)
- pathological responses(approx. 22 month)
- relapse-free survival (RFS)(approx. 22 month)
- Progression-free survival (PFS)(approx. 2 years)
- perioperative morbidity and mortality(60 days)
- Overall Survival (OS)(approx. 22 month)
- Tolerability(10 month)