342 Background: NabP+GEM chemotherapy improves survival compared with standard GEM monotherapy as treatment for advanced PDAC. A PDAC mouse model showed that delivery of nabP prior to GEM generated a higher intratumoural dFdC:dFdU ratio, which correlated with improved outcome. Therefore, scheduling may be critical to optimise clinical benefit. Methods: Patients were randomised to receive nabP+GEM, either concomitantly (CON) or sequentially (SEQ), 24 hours apart. After 6 cycles, patients benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) assessed by 8-weekly CT scanning; secondary endpoints included safety, response rate, overall survival (OS) and quality of life (QoL). Results: Between March 2014 and 2016, 146 patients (71 SEQ, 75 CON) from 19 UK sites were randomly assigned. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% of patients), 80 (27%), 90 (38%) or 100 (24%); 47% of primary tumours were situated in the pancreatic head; 84% had liver metastases. Median number of cycles was 4 SEQ, 3 CON; 50 patients (34%) received ≥ 6 cycles of treatment (41% SEQ, 28% CON). A 24+2hr interval was achieved in over 90% SEQ administrations. Most patients stopped treatment prior to 6 cycles due to disease progression/death (42%) or toxicity (41%). Grade ≥ 3 adverse events experienced by ≥ 10% patients (SEQ, CON) were neutropaenia (54%, 30%), febrile neutropaenia (12%, 12%), fatigue (22%, 16%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered to 35 patients (23 SEQ, 12 CON). To date, 109 patients have died. 6-month PFS by SEQ and CON arms was 46.7% and 33.8%; median PFS was 5.8 and 4.3 months. 12-month OS by SEQ and CON arms was 29.1% and 20.1%; median OS was 10.1 and 7.9 months. The objective response rate was 44% SEQ and 30% CON. Mean baseline QoL Global health status was 60.6 SEQ and 63.4 CON. The change from baseline (mean) at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP and GEM improves progression-free and overall survival. Although more myelosuppressive, QoL was maintained. Clinical trial information: ISRCTN71070888.
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