A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation

  • Joyce O’Shaughnessy
  • Angela DeMichele
  • Cynthia X. Ma
  • Paul Richards
  • Denise A. Yardley
  • Gail Shaw Wright
  • Kevin Kalinsky
  • Ronald Steis
  • Sami Diab
  • Gerard Kennealey
  • Ryan Geschwindt
  • Wei Jiang
  • Hope S. Rugo
Clinical trial
  • 87 Downloads

Abstract

Purpose

The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1).

Methods

Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS).

Results

Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran–Mantel–Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar–plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine.

Conclusions

The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

Keywords

Ruxolitinib Capecitabine Advanced HER2-negative Breast cancer Phase 2 Randomized study 

Notes

Acknowledgements

We thank the patients, their families, and their caregivers for participating in the trial. Medical writing assistance was provided by Abigail Marmont, Evidence Scientific Solutions Inc., Wilmslow, UK, and funded by Incyte Corporation.

Compliance with ethical standards

Conflict of interest

RG and WJ are employees of Incyte Corporation. GK is a contractor for Incyte Corporation. AD has received research funding from Incyte (institutional). HSR received research funding from Incyte for this trial. JOS, CXM, PR, DAY, GSW, KK, RS, and SD have no financial relationship with Incyte.

Ethical Approval

The protocol and all amendments were reviewed and approved by qualified institutional review boards/independent ethics committees before enrollment of participants in the study at each site. This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Conference on Harmonisation Guidelines. All aspects of the ethics review were conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each subject in writing before protocol-specific screening tests were performed.

Supplementary material

10549_2018_4770_MOESM1_ESM.pdf (55 kb)
Supplementary material 1 (PDF 55 kb)
10549_2018_4770_MOESM2_ESM.pdf (121 kb)
Supplementary material 2 (PDF 120 kb)
10549_2018_4770_MOESM3_ESM.pdf (7 kb)
Supplementary material 3 (PDF 6 kb)

References

  1. 1.
  2. 2.
    Toss A, Venturelli M, Peterle C, Piacentini F, Cascinu S, Cortesi L (2017) Molecular biomarkers for prediction of targeted therapy response in metastatic breast cancer: trick or treat? Int J Mol Sci.  https://doi.org/10.3390/ijms18010085 PubMedPubMedCentralGoogle Scholar
  3. 3.
    Caffarel MM, Zaragoza R, Pensa S, Li J, Green AR, Watson CJ (2012) Constitutive activation of JAK2 in mammary epithelium elevates Stat5 signalling, promotes alveologenesis and resistance to cell death, and contributes to tumourigenesis. Cell Death Differ 19:511–522.  https://doi.org/10.1038/cdd.2011.122 CrossRefPubMedGoogle Scholar
  4. 4.
    Quintás-Cardama A, Kantarjian H, Cortes J, Verstovsek S (2011) Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 10:127–140.  https://doi.org/10.1038/nrd3264 CrossRefPubMedGoogle Scholar
  5. 5.
    Chang Q, Bournazou E, Sansone P et al (2013) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15:848–862CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51.  https://doi.org/10.1038/nri1995 CrossRefPubMedGoogle Scholar
  7. 7.
    Al Murri AM, Bartlett JM, Canney PA, Doughty JC, Wilson C, McMillan DC (2006) Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer. Br J Cancer 94:227–230.  https://doi.org/10.1038/sj.bjc.6602922 CrossRefPubMedGoogle Scholar
  8. 8.
    Dethlefsen C, Højfeldt G, Hojman P (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138:657–664.  https://doi.org/10.1007/s10549-013-2488-z CrossRefPubMedGoogle Scholar
  9. 9.
    McMillan DC (2013) The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev 39:534–540.  https://doi.org/10.1016/j.ctrv.2012.08.003 CrossRefPubMedGoogle Scholar
  10. 10.
    Jhaveri K, Teplinsky E, Silvera D et al (2016) Hyperactivated mTOR and JAK2/STAT3 pathways: molecular drivers and potential therapeutic targets of inflammatory and invasive ductal breast cancers after neoadjuvant chemotherapy. Clin Breast Cancer 16(113–122):e111.  https://doi.org/10.1016/j.clbc.2015.11.006 Google Scholar
  11. 11.
    Long KB, Tooker G, Tooker E, Luque SL, Lee JW, Pan X, Beatty GL (2017) IL6 receptor blockade enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma. Mol Cancer Ther 16:1898–1908.  https://doi.org/10.1158/1535-7163.MCT-16-0899 CrossRefPubMedGoogle Scholar
  12. 12.
    Quintás-Cardama A, Vaddi K, Liu P et al (2010) Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115:3109–3117.  https://doi.org/10.1182/blood-2009-04-214957 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    JAKAFI® (2017) (ruxolitinib) tablets [package insert]. Incyte Corporation, Wilmington, DE, 2017. www.jakafi.com/pdf/prescribing-information.pdf. Accessed 20 Dec 2017
  14. 14.
    JAKAVI® (2017) (ruxolitinib) tablets [summary of product characteristics]. Novartis Europharm Limited, Camberley, 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002464/WC500133223.pdf. Accessed 20 Dec 2017
  15. 15.
    XELODA® (2017) (capecitabine) tablets [package insert]. Genentech, South San Francisco, 2017. https://www.gene.com/download/pdf/xeloda_prescribing.pdf. Accessed 20 Dec 2017
  16. 16.
    Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, Osterwalder B (2001) Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92:1759–1768CrossRefPubMedGoogle Scholar
  17. 17.
    Blum JL, Jones SE, Buzdar AU et al (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485–493.  https://doi.org/10.1200/JCO.1999.17.2.485 CrossRefPubMedGoogle Scholar
  18. 18.
    Hurwitz HI, Uppal N, Wagner SA et al (2015) 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. J Clin Oncol 33:4039–4047.  https://doi.org/10.1200/JCO.2015.61.4578 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hammond ME, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795.  https://doi.org/10.1200/JCO.2009.25.6529 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wolff AC, Hammond ME, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013.  https://doi.org/10.1200/JCO.2013.50.9984 CrossRefPubMedGoogle Scholar
  21. 21.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247.  https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefPubMedGoogle Scholar
  22. 22.
    Guidance for Industry (2007) Clinical trial endpoints for the approval of cancer drugs and biologics. Food and Drug Administration (FDA). http://www.fda.gov/downloads/Drugs/…/Guidances/ucm071590.pdf. Accessed 15 Feb 2018
  23. 23.
    Marotta LL, Almendro V, Marusyk A et al (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24 stem cell–like breast cancer cells in human tumors. J Clin Invest 121:2723–2735.  https://doi.org/10.1172/JCI44745 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Al Murri AM, Wilson C, Lannigan A, Doughty JC, Angerson WJ, McArdle CS, McMillan DC (2007) Evaluation of the relationship between the systemic inflammatory response and cancer-specific survival in patients with primary operable breast cancer. Br J Cancer 96:891–895.  https://doi.org/10.1038/sj.bjc.6603682 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pierce BL, Ballard-Barbash R, Bernstein L et al (2009) Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 27:3437–3444.  https://doi.org/10.1200/JCO.2008.18.9068 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wen J, Ye F, Huang X, Li S, Yang L, Xiao X, Xie X (2015) Prognostic significance of preoperative circulating monocyte count in patients with breast cancer: based on a large cohort study. Medicine 94:e2266.  https://doi.org/10.1097/MD.0000000000002266 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang D, Duan L, Tu Z et al (2016) The Glasgow Prognostic Score predicts response to chemotherapy in patients with metastatic breast cancer. Chemotherapy 61:217–222.  https://doi.org/10.1159/000443367 CrossRefPubMedGoogle Scholar
  28. 28.
    Majello B, Arcone R, Toniatti C, Ciliberto G (1990) Constitutive and IL-6-induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J 9:457–465PubMedPubMedCentralGoogle Scholar
  29. 29.
    Harrison C, Kiladjian JJ, Al-Ali HK et al (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366:787–798.  https://doi.org/10.1056/NEJMoa1110556 CrossRefPubMedGoogle Scholar
  30. 30.
    Verstovsek S, Mesa RA, Gotlib J et al (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807.  https://doi.org/10.1056/NEJMoa1110557 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Harrison CN, Mesa RA, Kiladjian JJ et al (2013) Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol 162:229–239.  https://doi.org/10.1111/bjh.12375 CrossRefPubMedGoogle Scholar
  32. 32.
    Mesa R, Verstovsek S, Kiladjian JJ et al (2016) Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy. Eur J Haematol 97:192–200.  https://doi.org/10.1111/ejh.12707 CrossRefPubMedGoogle Scholar
  33. 33.
    Eton DT, Cella D, Yost KJ et al (2004) A combination of distribution- and anchor-based approaches determined minimally important differences (MIDs) for four endpoints in a breast cancer scale. J Clin Epidemiol 57:898–910.  https://doi.org/10.1016/j.jclinepi.2004.01.012 CrossRefPubMedGoogle Scholar
  34. 34.
    Twelves C, Cortés J, O’Shaughnessy J et al (2017) Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician’s choice: results from the randomised phase III BEACON trial. Eur J Cancer 76:205–215.  https://doi.org/10.1016/j.ejca.2017.02.011 CrossRefPubMedGoogle Scholar
  35. 35.
    Mesa RA, Cortes J (2013) Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol 6:79.  https://doi.org/10.1186/1756-8722-6-79 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Santos FP, Verstovsek S (2014) Efficacy of ruxolitinib for myelofibrosis. Expert Opin Pharmacother 15:1465–1473.  https://doi.org/10.1517/14656566.2014.923404 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Joyce O’Shaughnessy
    • 1
  • Angela DeMichele
    • 2
  • Cynthia X. Ma
    • 3
  • Paul Richards
    • 4
  • Denise A. Yardley
    • 5
  • Gail Shaw Wright
    • 6
  • Kevin Kalinsky
    • 7
  • Ronald Steis
    • 8
  • Sami Diab
    • 9
  • Gerard Kennealey
    • 10
  • Ryan Geschwindt
    • 10
  • Wei Jiang
    • 10
  • Hope S. Rugo
    • 11
  1. 1.Baylor University Medical CenterTexas Oncology, US OncologyDallasUSA
  2. 2.Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Washington University School of MedicineSt LouisUSA
  4. 4.Oncology & Hematology Associates of Southwest Virginia, IncSalemUSA
  5. 5.Sarah Cannon Research Institute and Tennessee Oncology PLLCNashvilleUSA
  6. 6.Florida Cancer SpecialistsSt. PetersburgUSA
  7. 7.Columbia University Medical CenterNew YorkUSA
  8. 8.Northside Hospital, IncAtlantaUSA
  9. 9.Rocky Mountain Cancer CentersAuroraUSA
  10. 10.Incyte CorporationWilmingtonUSA
  11. 11.University of California San Francisco Comprehensive Cancer CenterSan FranciscoUSA

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