Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed

Abstract

Purpose Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. Patients and Methods In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m2 twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. Results In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation–based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). Conclusion Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

“…Secondly, it would support the hypothesis that routine markers of the systemic inflammatory response, and in particular the mGPS, may aid in the identification and selection of patients likely to benefit from such targeted therapies (50). In keeping with such a scheme, one recent clinical trial of a JAK inhibitor in patients with metastatic pancreatic cancer found an increase in overall survival only in those patients with an elevated CRP or mGPS (51). Therefore, it is clear that markers of the host inflammatory response should be incorporated into future studies of agents targeting the IL-6/JAK/STAT3 pathway in cancer.…”

Perioperative treatment options in resectable pancreatic cancer - how to improve long-term survival

“…The fact that therapies with a broader mechanism of action will become available for research projects in the near future is equally important. In addition to the omnipresent immunotherapy, stromal depletion, e.g., with hyaluronidase [55] and anti-inflammatory concepts [56] , appear most promising.…”

Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer?

“…In preclinical pancreatic cancer models, the JAK/STAT and related inflammatory pathways were found to drive cancer progression. Ruxolitinib is a JAK 1/2 inhibitor which has been evaluated in refractory pancreatic cancer with or without capecitabine in a randomized phase II study (65). In a pre-specified subgroup of patients with systemic inflammation as measured by elevated serum C-reactive protein (CRP >13 mg/L), survival significantly favored the ruxolitinib arm (3 and 6 months survivals of 48% and 42% vs. 29% and 11%, respectively).…”