Phase I trial of nab-paclitaxel administered concurrently with radiotherapy in patients with locally advanced inoperable pancreatic adenocarcinoma (ART in LAP).
e16796 Background: Locally advanced pancreatic adenocarcinoma (LAPC) carries a poor prognosis with median overall survival of 12-18m. The optimal treatment is controversial. Nab-paclitaxel is active in advanced pancreatic cancer and has exhibited radio-sensitising anti-tumour efficacy. Methods: We conducted an investigator-initiated open-label, phase-I dose escalation trial of nab-paclitaxel with standard external beam radiotherapy (EBRT). All patients had biopsy-proven, untreated, localised, inoperable pancreatic adenocarcinoma; Patients received nab-paclitaxel on a weekly schedule for 6 weeks, concurrently with EBRT. A 3+3 cohort design was employed, with doses of nab-paclitaxel increasing from 25 mg/m2 (cohort 1), to 50 mg/m2 (cohort 2), 75 mg/m2 (cohort 3) and 100 mg/m2 (cohort 4). This principal objective of the trial was to establish the maximum tolerated dose (MTD) of nab-paclitaxel given concurrently with radiotherapy. Secondary objectives included safety and efficacy evaluation, including response rate, median PFS, median and 1- year OS. Results: Fourteen patients were recruited to the study, with a median age of 69 (range 40-86). 69% had a head or neck of pancreas tumour. Majority of patients had grade 1 or 2 toxicities with nausea (92%), fatigue (69%), diarrhoea (54%) and vomiting (54%) being the most common. Three patients were recruited in each of the first three cohorts, without any dose limiting toxicities (DLT). In cohort 4, DLT of febrile neutropenia and enterocolitis was observed in patient 1. The cohort was expanded with a subsequent DLT of febrile neutropenia and enterocolitis observed in patient 5. Both DLT events lead to death (grade 5). The MTD and recommended phase II study dose has been established as 75mg/ m2. The disease control (PR and SD) rate was 67%, median PFS 4.7 months (95% CI 2.5-27.5), 1 year OS 43% and median OS 11.4 months (95%CI 6.37-25.2). Conclusions: The combination of weekly nab-paclitaxel and fractionated radiation was generally well-tolerated at doses of nab-paclitaxel below 100 mg/m2. There were two treatment related DLTs leading to death in the nab-paclitaxel 100 mg/m2 cohort. The MTD and recommended phase II study dose for nab-paclitaxel combined with radiation therapy in the treatment of LAPC is 75mg/m2. Clinical trial information: ACTRN12613001013752 .