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.

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.

• Authors: Shahneen K Sandhu, Kyri Papadopoulos, Peter C Fong, Amita Patnaik, Christina Messiou, David Olmos, George Wang, Brenda J Tromp, Thomas A Puchalski, Frances Balkwill, Birge Berns, Shobha Seetharam, Johann S de Bono, Anthony W Tolcher
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 4 Pg. 1041-50 (Apr 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23385782 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Broadly Neutralizing Antibodies
• Chemokine CCL2 (antagonists & inhibitors)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)