Sandhu, S. K., Papadopoulos, K., Fong, P. C., Patnaik, A., Messiou, C., Olmos, D., Wang, G., Tromp, B. J., Puchalski, T. A., Balkwill, F., Berns, B., Seetharam, S., de Bono, J. S., Tolcher, A. W. (2013) 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 CHEMOTHERAPY AND PHARMACOLOGY, 71 (4). pp. 1041-1050. ISSN 0344-5704

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Abstract

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 IgG1 kappa mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic-pharmacodynamic profile, and antitumor activity. 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. 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. Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.

Item Type:	Article
Authors (ICR Faculty only):	De-Bono, Johann
All Authors:	Sandhu, S. K., Papadopoulos, K., Fong, P. C., Patnaik, A., Messiou, C., Olmos, D., Wang, G., Tromp, B. J., Puchalski, T. A., Balkwill, F., Berns, B., Seetharam, S., de Bono, J. S., Tolcher, A. W.
Additional Information:	ISI Document Delivery No.: 114MM Times Cited: 0 Cited Reference Count: 36 Sandhu, Shahneen K. Papadopoulos, Kyri Fong, Peter C. Patnaik, Amita Messiou, Christina Olmos, David Wang, George Tromp, Brenda J. Puchalski, Thomas A. Balkwill, Frances Berns, Birge Seetharam, Shobha de Bono, Johann S. Tolcher, Anthony W. Janssen Research Development; Johnson Johnson 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 Bio-tech Oncology Research & Development, now called Janssen Research & Development.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. Springer New york
Uncontrolled Keywords:	Carlumab CC-chemokine ligand 2 CC-chemokine receptor 2 Phase I Solid tumors monocyte chemoattractant protein-1 resistant prostate-cancer cell leukemia-lymphoma macrophage infiltration rheumatoid-arthritis clinical-trials ovarian-cancer expression guidelines growth
Research teams:	ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Alexander Smithson
Date Deposited:	15 May 2013 15:48
Last Modified:	11 Jul 2017 09:02
URI:	http://publications.icr.ac.uk/id/eprint/12451

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