P-231 Interim results of a phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2)

Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM), cisplatin, and durvalumab. Although there is no firmly established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, GEM/nab-paclitaxel, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. The ABC-06 study showed that FOLFOX demonstrated a survival benefit over best supportive care in pts with previously treated advanced BTC. The NIFTY trial (South Korea) demonstrated a survival benefit of FU/LV/nal-IRI over FU/LV in this population (8.6 vs. 5.3 months); however, the NALIRICC trial (Germany) did not show a survival benefit (6.9 vs. 8.2 months). This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts receive nal-IRI 70 mg/m2 IV over 90 minutes, LV 400 mg/m2 IV over 30 minutes every 14 days, and FU 2400 mg/m2 over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS4mo to 50% or higher. We use a 2-stage Simon Minimax design. Seven of 19 patients in stage 1 must be alive and progression-free at 4 months for stage 2 to open. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled. Enrollment began in Q2 2019. Twenty-five pts have been enrolled. Six pts came off study due to toxicity prior to 4 months on study and were replaced to evaluate the PFS4mo endpoint. Of 19 evaluable patients, 8 patients were alive and progression-free at 4 months, meeting the criteria to open stage 2. With a median follow up of 8.1 months, median time to disease progression or study discontinuation due to toxicity for all patients was 3.9 months (95% CI 1.91-5.52, PFS4mo 46%), and for patients evaluable for the primary endpoint, the median PFS was 3.5 months (95% CI 1.84-5.52, PFS4mo 42%). Median OS was 9.5 months (95% CI 5.39-16.11). Adverse events were consistent with known toxicities from the FU/LV/nal-IRI regimen. FU/LV/nal-IRI appears to be an effective and tolerable treatment regimen for patients with previously-treated advanced BTC in a Western population, including 4 pts with PFS of 7 months or longer. Correlative studies evaluating longitudinal circulating tumor DNA analyses using banked blood specimens are planned. Enrollment in stage 2 is ongoing (NCT04005339).