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

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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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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Authors and Affiliations

  1. University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Room 7308, Ann Arbor, MI, 48109, USA
    Kenneth J. Pienta
  2. Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
    Jean-Pascal Machiels
  3. Ziekenhuisnetwerk Antwerpen-Middelheim, Antwerp, Belgium
    Dirk Schrijvers
  4. FGU Hertzen Oncology Research Institute of Rosmedtechnology, Moscow, Russia
    Boris Alekseev
  5. Russian Scientific Center of Radiology and Surgical Technologies, Federal Agency for High Technology Medical Care, St. Petersburg, Russia
    Mikhail Shkolnik
  6. University of Southampton Faculty of Medicine, Southampton, UK
    Simon J. Crabb
  7. Janssen Research & Development, Spring House, PA, USA
    Susan Li & Thomas A. Puchalski
  8. Janssen Research & Development, Radnor, PA, USA
    Shobha Seetharam & Chris Takimoto
  9. Janssen Research & Development, Raritan, NJ, USA
    Yusri Elsayed & Fitzroy Dawkins
  10. Royal Marsden, NHS Foundation Trust and the Institute of Cancer Research, Sutton, UK
    Johann S. de Bono

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  1. Kenneth J. Pienta
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  2. Jean-Pascal Machiels
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  3. Dirk Schrijvers
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  4. Boris Alekseev
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  5. Mikhail Shkolnik
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  6. Simon J. Crabb
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  7. Susan Li
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  8. Shobha Seetharam
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  9. Thomas A. Puchalski
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  10. Chris Takimoto
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  11. Yusri Elsayed
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  12. Fitzroy Dawkins
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  13. Johann S. de Bono
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Correspondence toKenneth 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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