Preoperative mFOLFIRINOX (or Gem-Nab-P) +/- Isotoxic High-dose SBRT for Borderline Resectable Pancreatic Adenocarcinoma

• Status: Not yet recruiting
• Trial end date: 2025-12-31
• Target enrollment: 0
• Participant gender: All

Summary

Background:Surgical resection is the only potentially curative treatment for patients with pancreatic cancer with the aim of curative R0 resection and related improvement of survival. As a standard, surgery is usually followed by adjuvant therapy that improves survival but neoadjuvant therapy (NAT) is a rapidly emerging concept that needs to be explored and validated in terms of therapeutic options, in both resectable and borderline resectable pancreatic tumors. In this setting, preoperative FFX seems to be feasible and can be prolonged by radiation therapy (chemoRT or SBRT) with promising benefits for patients in terms of R0 resection, local control and prolonged survival. However, the exact and best therapeutic sequence is not yet known and the additional role of adding radiation therapy to chemotherapy requires validation in randomised trials. We recently reported the feasibility and preliminary efficacy data of the whole therapeutic sequence combining preoperative FFX x 8 cycles (G-Nab-P in case of intolerance or no response ) prolonged by 5 days SBRT (35 Gy + SIB up to 50Gy at the tumour-vessel interfaces )[1, manuscript submitted]. We propose now to evaluate the impact and efficacy of adding isotoxic high-dose SBRT to preoperative neoadjuvant mFFX or Gem-NabP in patients with borderline or high-risk resectable pancreatic adenocarcinoma. We hypothesize that this full sequence strategy of pre-operative treatment is safe and feasible and will improve both the R0 resection rate and prognosis (DFS as primary end point) of pancreatic adenocarcinoma, especially by targeting the tumoural vascular encasement.

Objectives/endpoints: Evaluation of the safety and efficacy of pre-operative 8 cycles of modified FOLFIRINOX (or Gem-Nab-P) followed or not by SBRT in patients with borderline or at risk resectable pancreatic adenocarcinoma.

Primary objective:

• To compare DFS between arms

Secondary objectives:

To compare between the study arms:

• Resection rate

• R0 resection rate (> 1 mm)

• Overall survival (OS)

• Locoregional failure free interval (LFFI)

• Distant metastases free interval (DMFI)

• Complete feasibility of the therapeutic sequence

• Pathologic complete response rate (pCR)

• Toxicity (early and late)

• Postoperative complications rate

• Quality of life (QoL) assessment

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Erasme University Hospital
• Collaborators: Academisch Ziekenhuis Groningen; Belgian Group of Digestive Oncology; Chirec; Pôle Hospitalier Jolimont; Universitair Ziekenhuis Brussel; University Hospital St Luc, Brussels; University Hospital, Ghent
• Treatments: Albumin-Bound Paclitaxel; Gemcitabine

Criteria

Inclusion Criteria:

• Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinated process or body. Diagnosis should be verified by local pathologist

• cTNM stage: T1-4N0-2M0

• Confirmation of clinical and radiographic stage as borderline or at risk resectable* determined centrally by review of a diagnostic multisliced triphasic CT scan and/or MRI scan with contrast by a multidisciplinary board, composed by a dedicated oncological surgeon, radiologist and GI oncologist

• Age > 18 years old

• No prior chemotherapy or radiation for pancreatic cancer unless the neoadjuvant regimen as described

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• No grade ≥ 2 neuropathy

• Laboratory parameters as follows:

• Absolute neutrophil count (ANC) ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9 g/dL

• Creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated GFR > 45 mL/min

• Bilirubin ≤ 1.5 x ULN, including after adequate biliary stenting with metal stent (ideally 4 cm length)

• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5x ULN

• CA 19.9 < 2500 kU/l (baseline and absence of cholestasis)

• High-risk features for resectable disease as defined by NCCN (version 2.2021) and ASCO criteria, including: any vascular encasement, elevated CA 19.9, poor (nutritional) condition, large tumor (> 4cm) and/or involved loco-regional LN at CT, MRI or PET.

Exclusion Criteria:

• Evidence of extrapancreatic disease on diagnostic imaging (CT, MRI or PET scan), histologically proven or at laparoscopy, including distal nodal involvement beyond the peripancreatic tissues (including non-regional lymph node involvement, ie: proven involvement of precaval lumbar lymphadenopathy(ies) and/or distant metastases

• Locally advanced disease as defined by the NCCN criteria (version 2.2021) ie > 180° arterial encasement (SMA and CA) unreconstructible venous encasement (SMV/PV) due to tumor involvement or occlusion of a long segment.

• CA 19.9 > 2500 kU/l (baseline and absence of cholestasis)

• Contraindication of surgery (general)

• Contraindications to receive FFX or gemcitabine-nab-Paclitaxel

• History of radiotherapy of the upper abdomen

• Prior treatment with oxaliplatin, irinotecan, fluoruouracil or capecitabin

• Patient < 18 years old

• Major surgery within 4 weeks of study entry

• Uncontrolled pre-existing disease including, but not limited to: active infection, symptomatic congestive heart failure, unstable angina, social / psychiatric disorder that would limit compliance to treatment and good understanding of the informed consent form

• Other concurrent anticancer therapies

• Existence of another active neoplasia other than basal cell carcinoma of the skin, cervical carcinoma in situ or non-metastatic prostate cancer. Patients who have a history of neoplasia must have been in remission for more than 5 years to be included in the protocol

• Pregnant or breastfeeding women; for women of childbearing potential only, a negative pregnancy test done < 7 days prior to registration is required. Using of reliable contraception for at least 1 month before treatment is mandatory

• Chronic concomitant treatment with strong inhibitors of cytochrome p450, family 3, subfamily a, polypeptide 4 gene (CYP3A4) is not allowed on this study; patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study

Additional exclusion criteria before randomisation:

• Progressive disease (RECIST or PETCT, including non locoregional nodal involvement and increase of CA 19.9 by 20%) after receiving 4 cycles of FFX (or G/NP), including shift chemotherapy in case of early progression.

• Presence of unmanageable toxicity during the first part of neoadjuvant chemotherapy (first 4 cycles or 6 doses of FFX or G/NP, respectively.

• Pancreatic tumour > 6.0 cm in greatest axial dimension at the time of randomization

• Massive invasion of the stomach or intestines and/or direct intestinal invasion of the mucosae visible at ultrasoundendoscopy

• Active gastric or duodenal ulcer disease at the time of randomization. Tolerated in case of antecedent without active ulcer (confirmation by endoscopy before SBRT)