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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 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer
Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer
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 IgG(1)? 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-?g/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.
0167-6997
Pienta, Kenneth J.
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Machiels, Jean-Pascal
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Schrijvers, Dirk
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Alekseev, Boris
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Shkolnik, Mikhail
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Crabb, Simon J.
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Li, Susan
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Seetharam, Shobha
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Puchalski, Thomas A.
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Takimoto, Chris
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Elsayed, Yusri
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Dawkins, Fitzroy
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de Bono, Johann S.
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Pienta, Kenneth J.
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Machiels, Jean-Pascal
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Schrijvers, Dirk
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Alekseev, Boris
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Shkolnik, Mikhail
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Crabb, Simon J.
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Li, Susan
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Seetharam, Shobha
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Puchalski, Thomas A.
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Takimoto, Chris
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Elsayed, Yusri
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Dawkins, Fitzroy
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de Bono, Johann S.
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Pienta, Kenneth J., Machiels, Jean-Pascal, Schrijvers, Dirk, Alekseev, Boris, Shkolnik, Mikhail, Crabb, Simon J., Li, Susan, Seetharam, Shobha, Puchalski, Thomas A., Takimoto, Chris, Elsayed, Yusri, Dawkins, Fitzroy and de Bono, Johann S. (2012) Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Investigational New Drugs. (doi:10.1007/s10637-012-9869-8). (PMID:22907596)

Record type: Article

Abstract

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 IgG(1)? 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-?g/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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e-pub ahead of print date: 21 August 2012
Organisations: Cancer Sciences

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Local EPrints ID: 342452
URI: https://eprints.soton.ac.uk/id/eprint/342452
ISSN: 0167-6997
PURE UUID: 7334f1cc-0bb1-4628-95bc-6a01037ab0c5

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Date deposited: 30 Aug 2012 09:07
Last modified: 18 Jul 2017 05:28

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Contributors

Author: Kenneth J. Pienta
Author: Jean-Pascal Machiels
Author: Dirk Schrijvers
Author: Boris Alekseev
Author: Mikhail Shkolnik
Author: Simon J. Crabb
Author: Susan Li
Author: Shobha Seetharam
Author: Thomas A. Puchalski
Author: Chris Takimoto
Author: Yusri Elsayed
Author: Fitzroy Dawkins
Author: Johann S. de Bono

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