Clinical trial NCT05083247: Preoperative mFOLFIRINOX (or Gem-Nab-P) +/- Isotoxic High-dose SBRT for Borderline Resectable Pancreatic Adenocarcinoma
Official title: Preoperative Treatment With mFOLFIRINOX (or Gem-Nab-P) +/- Isotoxic High-dose Stereotactic Body Radiation Therapy (iHD-SBRT) for Borderline Resectable Pancreatic Adenocarcinoma: a Randomised Phase II Study (STEREOPAC)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pancreatic Neoplasm
Pancreatic Adenocarcinoma
Borderline Resectable Pancreatic Adenocarcinoma
Keywords: borderline resectable pancreatic cancer
neoadjuvant therapy
stereotactic body radiation therapy
chemotherapy
Lead sponsor: Erasme University Hospital
Sponsor class: OTHER
Collaborators: name: Jules Bordet Institute
name: Belgian Group of Digestive Oncology
name: University Hospital St Luc, Brussels
First posted: 2021-10-19
Enrollment: 256
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: comparative randomised phase II
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion criteria:

* 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)

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.
* 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)

Primary outcomes:
measure: Disease free survival
timeFrame: 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
measure: R0 Resection rate
timeFrame: up to 12 months
Secondary outcomes:
measure: Resection rate
timeFrame: up to 12 months
measure: Pathologic complete/major response (pCR)
timeFrame: up to 12 months
measure: Complete feasibility of the therapeutic sequence
timeFrame: up to 12 months
measure: Overall survival (OS)
timeFrame: Defined as the time interval between randomisation and death, assessed up to 60 months
measure: Locoregional failure free interval (LFFI)
timeFrame: defined as the time interval between the randomisation and the 1st documented date of locoregional failure, assessed up to 60 months
measure: Distant metastases free interval (DMFI)
timeFrame: defined as the period of time without distant metastasis after randomisation, assessed up to 60 months
measure: Toxicity, Incidence of adverse events
timeFrame: up to 24 months
measure: Postoperative complications
timeFrame: up to 12 months
measure: Quality of life (QoL) assessment - General
timeFrame: up to 24 months
measure: Quality of life (QoL) assessment - Pancreatic cancer
timeFrame: up to 24 months
measure: Quality of life (QoL) assessment - Depression
timeFrame: up to 24 months
measure: Technical and quality success rate of EUS-delivered fiducials.
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Uza Antwerp
city: Brussels
country: Belgium
facility: Hopital Erasme, HUB
city: Brussels
country: Belgium
facility: Jules Bordet Institute, HUB
city: Brussel
country: Belgium
facility: CHIREC
city: Brussel
country: Belgium
facility: Cliniques Universitaires St luc
city: Gent
country: Belgium
facility: UZ Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: La Louvière
country: Belgium
facility: Pôle Hospitalier Jolimont
city: Liège
country: Belgium
facility: Clinique Chc Montlégia
city: Mons
country: Belgium
facility: CHU Ambroise Paré
Study officials:
affiliation: Erasme Hospital, ULB
name: Jean-Luc Van Laethem, MD
role: STUDY_CHAIR
affiliation: Jules Bordet Institute
name: Christelle Bouchart, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.