A randomized double-blind phase 2 study of ruxolitinib (RUX) or placebo (PBO) with capecitabine (CAPE) as second-line therapy in patients (pts) with metastatic pancreatic cancer (mPC).

Abstract

4000 Background: Local and systemic inflammation (INFL) are hallmarks of cancer, including PC, that adversely impact prognosis. Given the role of JAK-STAT signaling in cancer INFL, the efficacy and safety of RUX, a JAK1/JAK2 inhibitor, given with CAPE in pts with mPC refractory to initial therapy was explored. Methods: Pts with adequate performance status and organ function who progressed after gemcitabine treatment were included. RUX + CAPE was well tolerated in a 9 pt safety run-in. Subsequently, 127 pts were randomized to CAPE 1000 mg/m2 BID days 1–14 with either RUX 15 mg BID or PBO on days 1–21 of a 21-day cycle. The primary endpoint was OS; secondary endpoints included PFS and ORR. To detect a HR ≤0.6 with 2-sided α=0.2 and β<0.2, final analysis was planned to occur after 97 deaths. Subgroup analyses were prespecified to explore treatment heterogeneity and a hypothesis that RUX would preferentially benefit pts with evidence of INFL. Results: In the randomized population, OS and PFS favored RUX (Table). Confirmed ORR was 7.8% for RUX and 0% for PBO. In a prespecified subgroup of pts with INFL, as measured by serum C-reactive protein (CRP > group median of 13 mg/L), OS significantly favored RUX over PBO (Table). In this subgroup, 3 and 6 month survival was 48% and 42% with RUX vs 29% and 11% with PBO, respectively. In pts with CRP ≤13 mg/L, significant benefits in OS or PFS were not observed (HR = 0.89 and 0.82, respectively). OS benefit was also seen in pts classified by modified Glasgow Prognostic Score (mGPS), a measure of INFL in cancer (HRs 0.91, 0.71, 0.49 for mGPS 0, 1, 2, respectively). The combination of RUX and CAPE was generally well tolerated. Grade 3 or 4 (G3/4) adverse events occurred in 75% and 82% of RUX and PBO pts, respectively. G3/4 neutropenia and thrombocytopenia were uncommon in RUX pts (1.7% and 0%, respectively). G3/4 anemia occurred more frequently on RUX (15.3%) than PBO (1.7%). Conclusions: RUX may improve OS and PFS in mPC pts with INFL characterized by elevated CRP or mGPS of 1 or 2. Clinical trial information: NCT01423604. HR (95% CI) RUX PBO Randomized, n 64 63 OS 0.79 (0.53–1.18) p=0.25 PFS 0.75 (0.52–1.10) p=0.28 CRP >13 mg/L, n 31 29 OS 0.47 (0.26–0.85) p=0.01 PFS 0.62 (0.35–1.1) p=0.20