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

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 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.

• Authors: Kenneth J Pienta, Jean-Pascal Machiels, Dirk Schrijvers, Boris Alekseev, Mikhail Shkolnik, Simon J Crabb, Susan Li, Shobha Seetharam, Thomas A Puchalski, Chris Takimoto, Yusri Elsayed, Fitzroy Dawkins, Johann S de Bono
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 3 Pg. 760-8 (Jun 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 22907596 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Antineoplastic Agents
• Broadly Neutralizing Antibodies
• CCL2 protein, human
• Chemokine CCL2
• carlumab

Topics

• Aged
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Broadly Neutralizing Antibodies
• Cell Count
• Chemokine CCL2 (blood, immunology)
• Endothelial Cells (cytology)
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplastic Cells, Circulating
• Orchiectomy
• Prostatic Neoplasms (blood, drug therapy, pathology)