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

Study Overview

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

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 borderline resectable pancreatic tumors. In this setting, preoperative FFX seems to be feasible and can be prolonged by radiation therapy. However, the exact and best therapeutic sequence is not yet known and the additional role of adding isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) to chemotherapy requires validation in randomised trials. We propose to evaluate the impact and efficacy of adding iHD-SBRT to preoperative neoadjuvant mFFX or Gem-NabP in patients with borderline resectable pancreatic adenocarcinoma.

STEREOPAC is an multicenter, academic, prospective, randomised comparative, interventional study. Patients receive 4 cycles of mFOLFIRINOX (or Gem-Nab-P)*. A full restaging (clinical, morphologic imaging, vascular involvement, biologics, CA 19.9) is performed. Non-progressive patients will be randomised (1:1) to ARM A for receiving 4 additional cycles of chemo followed by surgery. or to ARM B for receiving 5th and 6th cycles of chemo then iHD-SBRT followed by a 7th (and optional 8th cycle) followed by surgery. *: in case of CI or intolerance to mFFX, Gem-Nab-P regimen can be chosen or shifted to for 6 doses, then restaging, and then 3 doses followed by SBRT or 6 doses and immediate surgery) Adjuvant chemotherapy administration is indicated unless the patient's condition precludes it.

Pancreatic Neoplasm
Pancreatic Adenocarcinoma
Borderline Resectable Pancreatic Adenocarcinoma

DRUG: mFOLFIRINOX or Gemcitabine nab-paclitaxel
RADIATION: Isotoxic High-Dose (iHD)-SBRT
PROCEDURE: Surgery

ERA 001

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2021-09-29	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-05-22
First Submitted that Met QC Criteria 2021-10-15	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-05-23
First Posted (ACTUAL) 2021-10-19	Results First Posted N/A	Last Verified 2023-03

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Arm A mFOLFIRINOX (oxaliplatin: 85 mg/m2, CPT-11: 165-180 mg/m2, folinic acid: 400mg/m2 and 5FU 2000-2400 mg/m2/46 h) regimen for 8 cycles every 2 weeks; or*Gemcitabine-Nab-P: gem: 1000 mg/m2 weekly 3 w/4; nab-P: 125 mg/m2 3 w/4 for 4 cycles in case of unfit fo	DRUG: mFOLFIRINOX or Gemcitabine nab-paclitaxel oxaliplatin IV, irinotecan IV, leucovorin IV and 5-FU IV OR Gemcitabine IV Nab paclitaxel PROCEDURE: Surgery Surgery
EXPERIMENTAL: Arm B mFOLFIRINOX for 6 cycles (or for 3 cycles Gemcitabine-Nab-P: gem: 1000 mg/m2 weekly 3 w/4; nab-P: 125 mg/m2 3 w/4 in case of unfit for mFFX) +Isotoxic high-dose SBRT: 5 x 7Gy with Simultaneous Integrated Boost (SIB) up to maximum 55Gy (= 1 week; starting	DRUG: mFOLFIRINOX or Gemcitabine nab-paclitaxel oxaliplatin IV, irinotecan IV, leucovorin IV and 5-FU IV OR Gemcitabine IV Nab paclitaxel RADIATION: Isotoxic High-Dose (iHD)-SBRT Radiation therapy PROCEDURE: Surgery Surgery

Participant Group/Arm

Intervention/Treatment

ACTIVE_COMPARATOR: Arm A

mFOLFIRINOX (oxaliplatin: 85 mg/m2, CPT-11: 165-180 mg/m2, folinic acid: 400mg/m2 and 5FU 2000-2400 mg/m2/46 h) regimen for 8 cycles every 2 weeks; or*Gemcitabine-Nab-P: gem: 1000 mg/m2 weekly 3 w/4; nab-P: 125 mg/m2 3 w/4 for 4 cycles in case of unfit fo

DRUG: mFOLFIRINOX or Gemcitabine nab-paclitaxel

oxaliplatin IV, irinotecan IV, leucovorin IV and 5-FU IV OR Gemcitabine IV Nab paclitaxel

PROCEDURE: Surgery

Surgery

EXPERIMENTAL: Arm B

mFOLFIRINOX for 6 cycles (or for 3 cycles Gemcitabine-Nab-P: gem: 1000 mg/m2 weekly 3 w/4; nab-P: 125 mg/m2 3 w/4 in case of unfit for mFFX) +Isotoxic high-dose SBRT: 5 x 7Gy with Simultaneous Integrated Boost (SIB) up to maximum 55Gy (= 1 week; starting

DRUG: mFOLFIRINOX or Gemcitabine nab-paclitaxel

oxaliplatin IV, irinotecan IV, leucovorin IV and 5-FU IV OR Gemcitabine IV Nab paclitaxel

RADIATION: Isotoxic High-Dose (iHD)-SBRT

Radiation therapy

PROCEDURE: Surgery

Surgery

Primary Outcome Measures	Measure Description	Time Frame
Disease free survival	Defined as time from randomisation to the first documentation of event where events considered are 1) disease progression, per RECIST, prior to surgery, 2) discovery of hepatic or peritoneal carcinomatosis during surgical exploration, 3) recurrent disease following R0-R1 surgery, or 4) death due to any cause.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 weeks
R0 Resection rate	Defined as the proportion of eligible randomised patients in whom a R0 resection was achieved during surgery after neoadjuvant treatment with FOLFIRINOX +/- iHD-SBRT. R0 resection indicates a microscopically margin-negative resection (>1 mm) from the inked margins (pancreatic transection, vascular and posterior circumferential resection margins).	up to 12 months

Secondary Outcome Measures	Measure Description	Time Frame
Resection rate	defined as the percentage of eligible randomised patients that underwent a curative-intent resection	up to 12 months
Pathologic complete/major response (pCR)	Defined as the proportion of patients in whom a pCR or a major (<10% of residual tumour cells) was confirmed by histopathologic review of the surgical specimen.	up to 12 months
Complete feasibility of the therapeutic sequence	Defined as the proportion of patient who performed completely the neoadjuvant therapeutic sequence with mFFX (or Gem-Nab-P) +/- iHD-SBRT until surgery (abdominal exploration with or without pancreatectomy). The therapeutic sequence will not be considered as feasible if less than 60% of patients do not complete it until surgery.	up to 12 months
Overall survival (OS)	Defined as the time interval between randomisation and death. 95% confidence interval will be estimated based on standard method.	Defined as the time interval between randomisation and death, assessed up to 60 months
Locoregional failure free interval (LFFI)	defined as the time interval between the randomisation and the date of locoregional failure. A locoregional failure is any progressive or recurrent pancreatic cancer in the original tumour location or the N1-2 lymph node areas	defined as the time interval between the randomisation and the 1st documented date of locoregional failure, assessed up to 60 months
Distant metastases free interval (DMFI)	defined as the period of time without distant metastasis after randomisation.	defined as the period of time without distant metastasis after randomisation, assessed up to 60 months
Toxicity, Incidence of adverse events	assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the Patient-Reported Outcomes version of the CTCAE	up to 24 months
Postoperative complications	defined according to the Clavien-Dindo classification and definitions of post-pancreatic surgery complications (pancreatic fistula, delayed gastric emptying and bleeding) by the International study group on Pancreatic Surgery.	up to 12 months
Quality of life (QoL) assessment - General	assessed per EORTC General Quality of life of Cancer patient questionnaire QLQ-C30 version 3.0 (minimum value: 30 - maximum value: 126; higher score associated with worse QoL outcome).	up to 24 months
Quality of life (QoL) assessment - Pancreatic cancer	assessed per EORTC Quality of life of Pancreatic Cancer patient questionnaire QLQ-PAN26 (minimum value: 26 - maximum value: 104; higher score associated with worse QoL outcome).	up to 24 months
Quality of life (QoL) assessment - Depression	assessed per the depression test : Patient Health Questionnaire-9 (PHQ-9; minimum value: 0 - maximum value: 27; higher score associated with worse QoL outcome)	up to 24 months
Technical and quality success rate of EUS-delivered fiducials.	The technical success is defined as at least one marker presumed to be inside the tumour at the end of the EUS procedure. The quality success is defined as a score equal or higher than 6/12 points based on the 5 items quality score defined in [Figueiredo M, Bouchart C et al 2021].	up to 12 months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Jean-Luc Van Laethem, MD PhD

Phone Number: 003225553714

Email: jl.vanlaethem@erasme.ulb.ac.be

Study Contact Backup

Name: Mia Persoons

Phone Number: 003225553016

Email: mia.persoons@erasme.ulb.ac.be

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Cytologic or histologic proof of adenocarcinoma of the pancreatic head or uncinated process or body or tail. Diagnosis should be verified by local pathologist
cTNM stage: T1-4N0-2M0
Confirmation of clinical and radiographic stage as borderline resectable (CT scan and/or MRI scan with contrast according to the NCCN criteria) 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
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
No grade ≥ 2 neuropathy
Laboratory parameters as follows:
Absolute neutrophil count (ANC) ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
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, prior to any therapy and absence of cholestasis)

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

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.
CA 19.9 > 1000 kU/l after neoadjuvant therapy.
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 > 7.0 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 iHD-SBRT)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Jules Bordet Institute
Belgian Group of Digestive Oncology
University Hospital St Luc, Brussels

Investigators

STUDY_CHAIR: Jean-Luc Van Laethem, MD, Erasme Hospital, ULB

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Figueiredo M, Bouchart C, Moretti L, Mans L, Engelholm JL, Bali MA, Van Laethem JL, Eisendrath P. EUS-guided placement of fiducial markers for stereotactic body radiation therapy in pancreatic cancer: feasibility, security and a new quality score. Endosc Int Open. 2021 Feb;9(2):E253-E257. doi: 10.1055/a-1324-2892. Epub 2021 Feb 3.
Bouchart C, Engelholm JL, Closset J, Navez J, Loi P, Gokburun Y, De Grez T, Mans L, Hendlisz A, Bali MA, Eisendrath P, Van Gestel D, Hein M, Moretti L, Van Laethem JL. Isotoxic high-dose stereotactic body radiotherapy integrated in a total multimodal neoadjuvant strategy for the treatment of localized pancreatic ductal adenocarcinoma. Ther Adv Med Oncol. 2021 Oct 19;13:17588359211045860. doi: 10.1177/17588359211045860. eCollection 2021.
Manderlier M, Navez J, Hein M, Engelholm JL, Closset J, Bali MA, Van Gestel D, Moretti L, Van Laethem JL, Bouchart C. Isotoxic High-Dose Stereotactic Body Radiotherapy (iHD-SBRT) Versus Conventional Chemoradiotherapy for Localized Pancreatic Cancer: A Single Cancer Center Evaluation. Cancers (Basel). 2022 Nov 22;14(23):5730. doi: 10.3390/cancers14235730.

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