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A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors

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Abstract

Purpose

The CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic–pharmacodynamic profile, and antitumor activity.

Methods

Patients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15 mg/kg by 90-min intravenous infusion on days 1, 28, and every 2 weeks thereafter (dose escalation) or 10 or 15 mg/kg every 2 weeks (dose-expansion). Pharmacodynamic assessments were also performed.

Results

Forty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1–2 fatigue (9 %), nausea (7 %), headache (7 %), vomiting (5 %), and pruritus (5 %). The recommended phase II dose was 15 mg/kg every 2 weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6–9.6 days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50 % and RECIST SD for 10.5 and 5 months, respectively. Two other patients had RECIST SD for 7.2 and 15.7 months.

Conclusions

Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.

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Acknowledgments

The authors thank Jennifer Han of Janssen Services, LLC for writing support and assistance in preparing the manuscript for publication and Linda Snyder of Janssen Research & Development for critical review of the preclinical information included in the manuscript. This work was supported by Ortho Biotech Oncology Research & Development, now called Janssen Research & Development.

Conflict of interest

Papadopoulos, Patnaik, and Balkwill received research funding from the sponsor to conduct the current study. Wang, Tromp, Puchalski, Berns, and Seetharam are employees of Janssen, own Johnson & Johnson stock, and/or are currently conducting research sponsored by Johnson & Johnson. De Bono has served in a consultant/advisory role for Johnson & Johnson. Tolcher has served in a consultant/advisory role for Janssen Global Services, LLC. All remaining authors have declared no conflicts of interest.

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Authors and Affiliations

  1. Drug Development Unit, Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Shahneen K. Sandhu, Peter C. Fong, Christina Messiou, David Olmos & Johann S. de Bono

  2. South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, TX, USA

    Kyri Papadopoulos, Amita Patnaik & Anthony W. Tolcher

  3. Biostatistics, Janssen Research & Development, Spring House, PA, USA

    George Wang

  4. Oncology, Janssen Biologics, B.V., Leiden, The Netherlands

    Brenda J. Tromp

  5. Biologics Clinical Pharmacology, Janssen Research & Development, Spring House, PA, USA

    Thomas A. Puchalski

  6. Barts Cancer Institute, Queen Mary University of London, London, UK

    Frances Balkwill

  7. Global Regulatory Affairs, Janssen-Cilag, High Wycombe, UK

    Birge Berns

  8. Biomarker Oncology, Janssen Research & Development, Spring House, PA, USA

    Shobha Seetharam

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  1. Shahneen K. Sandhu
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  2. Kyri Papadopoulos
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  3. Peter C. Fong
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  4. Amita Patnaik
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  5. Christina Messiou
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  6. David Olmos
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  7. George Wang
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  8. Brenda J. Tromp
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  9. Thomas A. Puchalski
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  10. Frances Balkwill
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  11. Birge Berns
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  12. Shobha Seetharam
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  13. Johann S. de Bono
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  14. Anthony W. Tolcher
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Corresponding author

Correspondence to Johann S. de Bono.

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Sandhu, S.K., Papadopoulos, K., Fong, P.C. et al. A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother Pharmacol 71, 1041–1050 (2013). https://doi.org/10.1007/s00280-013-2099-8

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  • DOI: https://doi.org/10.1007/s00280-013-2099-8

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