Monthly alternating NALIRIFOX and GnP for metastatic pancreatic ductal adenocarcinoma (AltCAP).

Abstract

TPS798 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a deadly disease with 5-year survival rates below 5%, highlighting the need for improved therapeutic approaches. Intratumoral heterogeneity in transcriptional subtypes contributes to variable chemotherapy sensitivity. Alternating chemotherapy can accelerate exposure to diverse mechanisms of action while mitigating cumulative toxicity and resistance. The SEQUENCE trial demonstrated improved survival (OS & PFS) and overall response rate using alternating mFOLFOX/GnP vs. GnP alone. NALIRIFOX, which demonstrated superior OS compared to GnP in the NAPOLI-3 trial, is now a Category 1 NCCN recommendation for first-line mPDAC. Alternating NALIRIFOX with GnP may improve outcomes and tolerability. Methods: AltCAP is a single-arm, open-label phase II trial for treatment-naïve mPDAC patients with ECOG PS 0–1. Patients receive three 56-day macrocycles (6 months total), each comprising a 28-day NALIRIFOX sub-cycle A followed by a 28-day GnP sub-cycle B. NALIRIFOX (sub-cycle A): liposomal irinotecan (50 mg/m²), leucovorin (400 mg/m 2 ), oxaliplatin (60 mg/m²), 5-FU (2400 mg/m² over 46 hrs) on Days 1 & 15. GnP (sub-cycle B): Gemcitabine (1000 mg/m²) + nab-paclitaxel (125 mg/m²) on Days 1, 8* (optional per tolerability), & 15. The study uses a Simon’s two-stage design targeting 41 patients. The trial activated in June 2025, with anticipated enrollment completion in Q4 2026. The primary endpoint is 6-month PFS. Secondary endpoints include ORR, OS, time to treatment failure, and treatment-related adverse events (per CTCAE v5.0). Exploratory endpoints include serial circulating tumor DNA (ctDNA) testing at baseline, each subcycle, and progression to monitor response and early relapse, plus retrospective correlation of transcriptional subtypes with clinical outcomes.