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Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer

  • PHASE II STUDIES
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Summary

Background CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. Methods In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. Results Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥3 AEs. Common grade ≥3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-μg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. Conclusion Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.

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References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29

    Article  PubMed  Google Scholar 

  2. Walczak JR, Carducci MA (2007) Prostate cancer: a practical approach to current management of recurrent disease. Mayo Clin Proc 82:243–249

    PubMed  Google Scholar 

  3. Lu Y, Cai Z, Xiao G et al (2007) CCR2 expression correlates with prostate cancer progression. J Cell Biochem 101:676–685

    Article  PubMed  CAS  Google Scholar 

  4. Garmey EG, Sartor O, Halabi S, Vogelzang NJ (2008) Second-line chemotherapy for advanced hormone-refractory prostate cancer. Clin Adv Hematol Oncol 6:118–132

    PubMed  Google Scholar 

  5. Tannock IF, de Wit R, Berry WR et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512

    Article  PubMed  CAS  Google Scholar 

  6. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF (2008) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26:242–245

    Article  PubMed  CAS  Google Scholar 

  7. de Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005

    Article  PubMed  Google Scholar 

  8. de Bono JS, Oudard S, Ozguroglu M et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376:1147–1154

    Article  PubMed  Google Scholar 

  9. Lu Y, Cai Z, Galson DL et al (2006) Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate 66:1311–1318

    Article  PubMed  CAS  Google Scholar 

  10. Mazzucchelli L, Loetscher P, Kappeler A et al (1996) Monocyte chemoattractant protein-1 gene expression in prostatic hyperplasia and prostate adenocarcinoma. Am J Pathol 149:501–509

    PubMed  CAS  Google Scholar 

  11. Lu Y, Xiao G, Galson DL et al (2007) PTHrP-induced MCP-1 production by human bone marrow endothelial cells and osteoblasts promotes osteoclast differentiation and prostate cancer cell proliferation and invasion in vitro. Int J Cancer 121:724–733

    Article  PubMed  CAS  Google Scholar 

  12. Loberg RD, Day LL, Harwood J et al (2006) CCL2 is a potent regulator of prostate cancer cell migration and proliferation. Neoplasia 8:578–586

    Article  PubMed  CAS  Google Scholar 

  13. Li X, Loberg R, Liao J et al (2009) A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone. Cancer Res 69:1685–1692

    Article  PubMed  CAS  Google Scholar 

  14. Loberg RD, Ying C, Craig M, Yan L, Snyder LA, Pienta KJ (2007) CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 9:556–562

    Article  PubMed  CAS  Google Scholar 

  15. Loberg RD, Ying C, Craig M et al (2007) Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67:9417–9424

    Article  PubMed  CAS  Google Scholar 

  16. Sandhu SK, Fong PC, Frentzas S et al (2009) First-in-human, first-in-class, phase I study of a human monoclonal antibody CNTO 888 to the CC-chemokine ligand 2 (CCL2/MCP-1) in patients with solid tumors. J Clin Oncol 27:e13500

    Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148–1159

    Article  PubMed  Google Scholar 

  19. Cancer Pain Relief with a Guide to Opioid Availability. (1996) World Health Organization, Geneva, Switzerland

  20. Cleeland CS (2006) The measurement of pain from metastatic bone disease: capturing the patient’s experience. Clin Cancer Res 12:6236s–6242s

    Article  PubMed  Google Scholar 

  21. Halabi S, Vogelzang NJ, Kornblith AB et al (2008) Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. J Clin Oncol 26:2544–2549

    Article  PubMed  Google Scholar 

  22. Danila DC, Heller G, Gignac GA et al (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13:7053–7058

    Article  PubMed  CAS  Google Scholar 

  23. de Bono JS, Scher HI, Montgomery RB et al (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302–6309

    Article  PubMed  Google Scholar 

  24. Haringman JJ, Gerlag DM, Smeets TJ et al (2006) A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 54:2387–2392

    Article  PubMed  CAS  Google Scholar 

  25. Puchalski T, Han C, McIntosh T et al. (2012) A novel preclinical study in cynomolgus monkeys examining CCL2 production rate and kinetic profile after escalating dose administration of anti-CCL2 human monoclonal antibody carlumab (CNTO 888). AACR Abstract #2518

  26. Fetterly GJ, Puchalski T, Takimoto C et al (2010) Utilizing mechanistic PK/PD modeling to simultaneously examine free CCL2, total CCL2, and CNTO 888 serum concentration time data. J Clin Oncol 28:3029, Abstract

    Google Scholar 

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Acknowledgments

This study was sponsored by Janssen Research & Development. The following investigators participated in the study: UK: Christian Ottensmeier, Janet Brown, Nicholas D. James; US: George Giels. The authors thank Bob Zhong of Janssen Research & Development for his involvement with the statistical design of the study and for critical review of the manuscript and Jennifer Han of Janssen Services, LLC for assistance in writing and preparing the manuscript.

Conflicts of interest

Kenneth J. Pienta has received research grants from and been a consultant for Centocor B.V. Dirk Schrijvers has received commercial research grants from Cougar, Johnson & Johnson, and Janssen Pharmaceuticals. Boris Alekseev has received commercial research grants. Susan Li, Shobha Seetharam, Thomas A. Puchalski, Chris Takimoto, Yusri Elsayed, and Fitzroy Dawkins are employees of Janssen, a subsidiary of Johnson & Johnson, and own Johnson & Johnson stock options. Johann S. de Bono has received honoraria and been a consultant/advisory board member for Johnson & Johnson.

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Correspondence to Kenneth J. Pienta.

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Pienta, K.J., Machiels, JP., Schrijvers, D. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest New Drugs 31, 760–768 (2013). https://doi.org/10.1007/s10637-012-9869-8

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  • DOI: https://doi.org/10.1007/s10637-012-9869-8

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