A phase 1/2, open-label, dose-expansion study of liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) in patients with previously untreated metastatic pancreatic cancer
nal-IRI+5-FU/LV is approved for patients with mPAC after disease progression following gemcitabine-based therapy. The current study (NCT02551991) is a phase 1/2, open-label trial to assess the safety, tolerability, and dose-limiting toxicities (DLTs) of nal-IRI+5-FU/LV+OX (NAPOX) for the first-line treatment of patients with mPAC and to determine phase 3 dosing.
Following 4 dose exploration cohorts (Part 1A), a recommended dose for dose expansion (Part 1B) was selected based on DLTs and cumulative safety (nal-IRI 50 mg/m2 [free-base equivalent; FBE], OX 60 mg/m2, LV 400 mg/m2, 5-FU 2400 mg/m2 on days 1 & 15 of each 28-day cycle). The expansion phase enrolled 25 patients at the selected dose level, with 32 subjects treated at the selected dose level (pooled population; PP 50/60). Patients were age ≥18 yrs with previously untreated locally advanced or mPAC, ECOG performance status ≤1, and adequate organ function. The primary endpoint was safety and tolerability, with secondary assessments based on 19/Feb/2019 data cut-off when all patients had completed their second scheduled tumor assessment after 16 weeks of treatment.
56 patients were enrolled and treated, with 32 patients from (n = 7) and; Dose Expansion Cohort (n = 25) included in the PP 50/60 analysis (n = 29 mPDAC; n=3 locally advanced PDAC). 9 DLTs were reported by 5 patients across the 4 dose exploration cohorts (diarrhea, n = 2; vomiting, anal fissure, anal inflammation, proctalgia, neutropenic infection, neutropenic sepsis, and febrile neutropenia, all n = 1), including 1 patient in (febrile neutropenia). Treatment-related TEAEs Grade 3 or higher were reported by 39 of 56 patients (50/60 PP, n = 20/32: neutropenia, n = 9; febrile neutropenia, hypokalemia, both n = 4; diarrhea, nausea, both n=3; anemia, vomiting, both n = 2), with no reported Grade 3 or higher fatigue or peripheral neuropathy. Serious adverse events (SAEs) were reported by 31 of 56 patients (50/60 PP, n = 14/32), with n = 23 patients reporting treatment-related SAEs (50/60 PP, n = 10/32 patients: nausea, febrile neutropenia, both n = 3; diarrhea, vomiting, both n = 2; colitis, enterocolitis, stomatitis, anemia, pneumonia, and pyrexia, all n = 1). 15 patients reported TEAEs leading to discontinuation (50/60 PP, n = 4/32), with 36 patients requiring dose adjustment due to AEs (50/60 PP, n = 23/32). 23 of 32 patients (71.9%) in the 50/60 PP achieved disease control at 16 weeks (DCR16wk). Best overall response in the 50/60 PP was complete response (CR) in 1 patient (diagnosed with locally advanced Stage III disease), partial response (PR) in 10 patients, and stable disease (SD) in 15/32 patients (sum of CR+PR+SD: 81.3%), with an overall response rate (ORR) of 34%. At data cut-off, 15/32 patients in the PP 50/60 remain on treatment. Preliminary analysis of median progression-free survival and median overall survival are not yet mature for evaluation.
In the first-line treatment of patients with mPAC, NAPOX (nal-IRI 50 mg/m2 (FBE), OX 60 mg/m2, LV 400 mg/m2, and 5-FU 2400 mg/m2) appears manageable, with promising anti-tumor activity (DCR16wk of 71.9%, sum of CR+PR+SD: 81.3%, and ORR of 34%) warranting further clinical assessment. This study is ongoing, with additional analyses planned.
