The combination of nab-paclitaxel and gemcitabine (AG) as well as FOLFIRINOX (FFX) represent effective therapeutic options for metastatic pancreatic adenocarcinoma (MPA). This investigation assessed a novel initial sequential approach (AG succeeded by FFX) in MPA, potentially mitigating resistance to the initial regimen and prolonging disease control. Individuals with confirmed MPA via histology or cytology participated in a multicenter study, receiving AG on days 1, 8, and 15, then FFX on days 29 and 43. During the phase Ib portion, three escalation levels were examined to determine the maximum tolerated dose (MTD) and the recommended dose for phase II. The phase II component primarily focused on objective response rate (ORR), with additional endpoints including tolerability, progression-free survival (PFS), and overall survival (OS). In phase Ib, 33 participants were enrolled (31 evaluable), with a median age of 61 years (42-75 years) and 54.8% male. Five dose-limiting toxicities occurred, with no fatalities. Key grade 3/4 adverse events included neutropenia resolving without intervention (35.5%/32.3%), venous thromboembolism (grade 3: 22.6%), and thrombocytopenia (grade 3: 29.0%); MTD was not attained. For phase II, 58 participants were included, median age 60 years (34-72 years), 50% male, and ECOG performance status 0 in 37.9% and 1 in 62.1%. They underwent a median of 4 cycles (1-9) over 8.5 months (0.5-19.8 months). ORR reached 64.9% [95% CI 51.1%-77.1%], with notably minimal neurotoxicity. Predominant grade 3-4 events were venous thromboembolism, thrombocytopenia, neutropenia/febrile neutropenia, nausea, diarrhea, weight reduction, and fatigue, without treatment-related deaths. Responses included complete in 3.5%, partial in 61.4%, stable disease in 19.3%, and progression in 15.8%. Median PFS was 10.5 months (95% CI 6.0-12.5 months), and median OS was 15.1 months (95% CI 10.6-20.1 months). The sequential regimen of AG followed by FFX demonstrated manageable toxicity in the first-line setting, without significant neurotoxicity constraints, alongside elevated response rates and encouraging survival outcomes that support pursuit of randomized comparative studies.
