Background: LAPC represents a major challenge with no standardized chemotherapy (CT) and radiotherapy (RT) treatment. Phase 2 studies (LAPACT/NEOLAP) indicated efficacy of FFX and GA, although addition of conventionally fractionated RT remains controversial. Phase 3 LAP07 trial obtained a reduction of progression free survival (PFS), albeit with no overall survival (OS) advantage. Since in metastatic pancreatic cancer we recently attained with GA/FFX sequential combination (GABRINOX) high objective response rate and promising OS with acceptable toxicity and no limiting neurotoxicity, we proposed in LAPC to complement GABRINOX with SMART, recently recognized beneficial in pancreatic tumors by a retrospective multicenter study (OS at 2 years) and our prospective registry study (dosimetric benefit of adaptation). In a first step (SEQ1), we will evaluate GABRINOX efficacy and select patients without progression for a second step (SEQ2), to evaluate feasibility and tolerance in patients without disease progression after SEQ1. Secondarily we will evaluate CT tolerance (SEQ1), acute toxicities and dosimetric results (SEQ2) and for both SEQ1+2, late toxicities, response to treatment, PFS, OS and quality of life (QoL). Methods: Naive patients with confirmed non-metastatic unresectable adenocarcinoma by centralized reading (WHO 0/1) and adequate organ function will receive in SEQ1 two cycles of GABRINOX, GA (1000 mg/m², 125 mg/m²) on days 1, 8, and 15 followed by FFX on day 29 and 43. After 3-4 weeks, patients without progression or unacceptable toxicity will benefit from SMART (5 fractions of 10 Gy/day over 5 consecutive days). Specific dummy-run, contouring quality assurance and dosimetric plans will precede post-treatment monitoring every 6 weeks for 6 months for non-progressive patients and then every 2 months until progression: radiological assessment, biological markers (circulating tumor DNA) and QoL evaluation. Co-primary endpoints include success of SEQ1 (non-progression at 4 months, RECIST v1.1) and that of SEQ2 as absence of acute digestive non-toxicity rate > grade 3 (NCI-CTCAE v5.0) within 90 days. Based on Fleming design with maximal inefficacy (p₀) of 70% and 90% (α = 2.5% and β = 5%) we need 98 and 70 patients (SEQ1 and SEQ2), and total of 103 cases considering those entering in SEQ 2 (70%) and non-evaluable patients. Success rate, toxicities (by treatment sequences) and safety (System Organ Class) by patient and cycle will be considered while dosimetry will be correlated with gastro-intestinal toxicities. Median follow-up, OS and PFS will be expressed as medians and rates with 95% CI while QoL will be explored by QLQ-C30 and QLQ-PAN26 analyses using the time to definitive deterioration. From 2021, we included 5 patients (NCT04570943). Clinical trial information: NCT04570943.