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      Randomized, double‐blind, phase two study of ruxolitinib plus regorafenib in patients with relapsed/refractory metastatic colorectal cancer

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          Abstract

          Background

          The Janus kinase/signal transducer and activator of transcription ( JAKSTAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer ( CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC.

          Methods

          In this two‐part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0‐2; received fluoropyrimidine, oxaliplatin, and irinotecan‐based chemotherapy, an anti‐vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild‐type (and no contraindication), an anti‐epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open‐label, safety run‐in phase (part 1; ruxolitinib 20 mg twice daily [ BID] plus regorafenib 160 mg once daily [ QD]), the double‐blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C‐reactive protein [ CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival ( OS).

          Results

          The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run‐in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression‐free survival ( PFS) between treatments in substudy 1 ( OS: hazard ratio [ HR] = 1.040 [95% confidence interval: 0.725‐1.492]; PFS: HR = 1.004 [0.724‐1.391]) and substudy 2 ( OS: HR = 0.767 [0.478‐1.231]; PFS: HR = 0.787 [0.576‐1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified.

          Conclusions

          Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/ PFS vs. regorafenib plus placebo.

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          Most cited references18

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          The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer.

          Since the initial work, a decade ago that the combination of C-reactive protein and albumin, the Glasgow Prognostic Score (GPS), had independent prognostic value in patients with cancer, there have been more than 60 studies (>30,000 patients) that have examined and validated the use of the GPS or the modified GPS (mGPS) in a variety of cancer scenarios. The present review provides a concise overview of these studies and comments on the current and future clinical utility of this simple objective systemic inflammation-based score. The GPS/mGPS had independent prognostic value in (a) unselected cohorts (4 studies, >19,400 patients) (b) operable disease (28 studies, >8,000 patients) (c) chemo/radiotherapy (11 studies, >1500 patients) (d) inoperable disease (11 studies, >2,000 patients). Association studies (15 studies, >2,000 patients) pointed to an increased GPS/mGPS being associated with increased weight and muscle loss, poor performance status, increased comorbidity, increased pro-inflammatory and angiogenic cytokines and complications on treatment. These studies have originated from 13 different countries, in particular the UK and Japan. A chronic systemic inflammatory response, as evidenced by the GPS/mGPS, is clearly implicated in the prognosis of patients with cancer in a variety of clinical scenarios. The GPS/mGPS is the most extensively validated of the systemic inflammation-based prognostic scores and therefore may be used in the routine clinical assessment of patients with cancer. It not only identifies patients at risk but also provides a well defined therapeutic target for future clinical trials. It remains to be determined whether the GPS has prognostic value in other disease states. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            A Confidence Interval for the Median Survival Time

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              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.

              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.
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                Author and article information

                Contributors
                dfogelman@mdanderson.org
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                19 August 2018
                November 2018
                : 7
                : 11 ( doiID: 10.1002/cam4.2018.7.issue-11 )
                : 5382-5393
                Affiliations
                [ 1 ] The University of Texas MD Anderson Cancer Center Houston Texas
                [ 2 ] Centro Integral Oncológico Clara Campal Madrid Spain
                [ 3 ] Hospital General Universitario Gregorio Marañón Madrid Spain
                [ 4 ] Hospital Universitario Virgen del Rocío Sevilla Spain
                [ 5 ] University of Toledo College of Medicine and Life Sciences Toledo Ohio
                [ 6 ] Oncology Hematology Care Cincinnati Ohio
                [ 7 ] University Hospital of Besançon Besançon France
                [ 8 ] Institut Sainte Catherine Avignon France
                [ 9 ] Hospital Universitario Central de Asturias Oviedo Spain
                [ 10 ] Rocky Mountain Cancer Centers Denver Colorado
                [ 11 ] Charleston Hematology Oncology Associates Charleston South Carolina
                [ 12 ] Incyte Corporation Wilmington, Delaware
                [ 13 ] Sarah Cannon Research Institute/Tennessee Oncology Nashville Tennessee
                Author notes
                [*] [* ] Correspondence: David Fogelman, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 ( dfogelman@ 123456mdanderson.org ).
                Article
                CAM41703
                10.1002/cam4.1703
                6246927
                30123970
                38883294-9b40-4dce-a07b-1756605c1e41
                © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 February 2018
                : 02 July 2018
                : 03 July 2018
                Page count
                Figures: 4, Tables: 4, Pages: 12, Words: 7335
                Funding
                Funded by: Incyte Corporation (Wilmington, Delaware)
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                cam41703
                November 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:21.11.2018

                Oncology & Radiotherapy
                clinical trial,colorectal cancer,inflammation,jak1 protein tyrosine kinase,jak2 protein tyrosine kinase,ruxolitinib

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