TPS4191 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.

3561 Background: Standard treatment options for RAS-mutated mCRC pts include the combination of bevacizumab with FOLFIRINOX, a three-drug chemotherapy regimen. Unlike bevacizumab, REGO – an oral multi-tyrosine kinase agent - exhibits not only antiangiogenic properties with cytostatic effects but also true cytotoxic effects. We report the preliminary results of the FOLFIRINOX-R trial (NCT03828799), in which we evaluated the safety and the efficacy of REGO in combination with FOLFIRINOX in pts with RAS-mutated mCRC. Methods: FOLFIRINOX-R trial is a prospective, dose-finding, phase I/II study whose dose-escalation part has been completed. Dose escalation was implemented following a 3 + 3 design and included three dose levels (DL). FOLFIRINOX regimen includes oxaliplatin (85 mg/m²), folinic acid (400 mg/m²), irinotecan (150–180 mg/m²), 5-fluorouracil (400 mg/m² in bolus then 2400 mg/m² over 46h), and was administered every 14 days. REGO (80 to 160 mg per day, as per DL) was administered on days 4 to 10 of each cycle. Treatment was continued up to 12 cycles or until progression or unacceptable toxicity. The primary objectives of the dose-finding part of the study were to determine the maximum tolerated dose (MTD) using as endpoint the incidence of DLTs during the three first cycles of treatment, and to select the recommended phase 2 dose (RP2D). Key eligibility criteria include ECOG PS ≤1 and RAS-mutated mCRC not amenable to surgery with curative intent and not previously treated for metastatic disease. Patients with the 7/7 variant of the UGT1A1*28 polymorphism were not eligible. Prophylactic G-CSF was administered from Day-7 to Day-12. Results: Thirteen pts were enrolled across the 3 DL (DL 1: 3 pts, DL 2: 6 pts, DL 3: 4 pts); 46% of pts were female, the median age was 65 yo [range: 40 ; 76]. One pt (at DL 3) was not evaluable for DLT because of poor observance during the first 2 cycles. At data cut-off, median treatment duration and median follow-up were 4.6 mo. (range: 2.3; 10) and 13.4 mo. (range: 3.8; 18.0), respectively. One DLT (a grade 3 hypokalaemia related to grade 2 diarrhoea) occurred at DL 2. MTD was not reached at DL 3 (REGO 160 mg/day). The most common grade ≥3 TRAE per patient were grade 3 neutropenia (n = 1), grade 4 neutropenia (n = 1), grade 3 neuropathy (n = 2) and grade 3 diarrhoea (n = 7). Dose reductions/discontinuations due to grade ≥3 TRAE were necessary in 12/13 (92%) pts. The ORR was 62% (95% CI 32%-86%) and median PFS was 9.1 mo (range: 3.1; 15.4). Conclusions: Full-dose FOLFIRINOX plus full-dose REGO (160mg/day, days 4 to 10) can be administered safely. Due to the manageable toxicity profile and the promising efficacy observed in the dose-escalation stage, this regimen deserves to be evaluated in the dose-expansion stage. Clinical trial information: NCT03828799.

No abstract

TPS4190 Background: PC is a major health concern worldwide and a deadly disease due to its high metastatic behavior. In recent years, incremental progresses have been made with the use of new chemotherapy (CT) regimen in the metastatic setting. Thus, both PRODIGE 4/ACCORD11 (Conroy T, et al. 2011) and MPACT (Von Hoff D, et al. 2013) phase III trials established 2 new standard-of-care in the first line treatment of metastatic PC (mPC), demonstrating a survival benefit over gemcitabine monotherapy, with the use of FFX or GA. In the phase I/II GABRINOX trial (Assenat E, et al. ESMO Open 2021), we reported that sequential GA followed by FFX provided a high overall response rate (ORR) (64.9%) and a promising median progression-free survival (PFS, 10.5 months) and median overall survival (OS, 15.1 months), together with acceptable toxicity and remarkably low severe neurotoxicity rate (gr.3: 5.3%). To follow up these encouraging results in a controlled study, we aimed at comparing our experimental GABRINOX regimen to control FFX in the GABRINOX-2 randomized phase 2 trial (NCT05065801). Our primary objective is PFS, and our secondary objectives are tolerance, ORR, disease-control rate, OS, and Quality-of-life. Methods: Main inclusion criteria were as follows: Patients (pts) in good condition (ECOG PS ≤ 1), aged from 18 to 75 yo, with histologically or cytological proven mPC and at least one measurable metastatic target. Pts should have not been treated with (adjuvant) chemotherapy in the last 6 months. Eligible pts are randomized (ratio 1:1) either in the standard FFX group or in the experimental GABRINOX group where a GA (gemcitabine 1000 mg/m² and Nab-paclitaxel 125 mg/m², day 1-8-15) cycle alternates after a 2-weeks rest with a FFX cycle. To detect an increase in median PFS from 6.4 to 10.5 months (HR = 0.61) with a 80% power and a 5% α risk, 130 events are required among a total population of 210 pts. PFS was defined as the length of time between randomization and the onset of 1st documented progression (RECIST 1.1 criteria) or death. The study of quality of life will use the EORTC QLQ-C30 and QLQ-PAN26 self-reported questionnaires at baseline and every 2 months up to 12 months and then at 16, 20 and 24 months. Circulating DNA tests will be carried out at baseline and every 2 months until progression. All numerical variables will be expressed as medians and 95% CI, while PFS and OS will be estimated using Kaplan-Meier method. Multivariate analyses will use Cox proportional hazard model. Enrolment started in late 2021 and 3 patients were included so far. Clinical trial information: NCT05065801.

No abstract