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.
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: David Bauer; Elizabeth Mazzio; Karam Fa Soliman; Equar Taka; Ebenezer Oriaku; Tracey Womble; Selina Darling-Reed Journal: Anticancer Res Date: 2014-06 Impact factor: 2.480
Authors: Daniel P Regan; Jonathan W Coy; Kirti Kandhwal Chahal; Lyndah Chow; Jade N Kurihara; Amanda M Guth; Irina Kufareva; Steven W Dow Journal: J Immunol Date: 2019-04-10 Impact factor: 5.422
Authors: Francois Moisan; Edgar B Francisco; Anamaria Brozovic; George E Duran; Yan C Wang; Shalini Chaturvedi; Shobha Seetharam; Linda A Snyder; Parul Doshi; Branimir I Sikic Journal: Mol Oncol Date: 2014-04-18 Impact factor: 6.603