title: 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: OBJECTIVE
  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: Drug Development Unit, Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors: Shahneen K
authors: SK
authors: Sandhu
authors: Kyri
authors: K
authors: Papadopoulos
authors: Peter C
authors: PC
authors: Fong
authors: Amita
authors: A
authors: Patnaik
authors: Christina
authors: C
authors: Messiou
authors: David
authors: D
authors: Olmos
authors: George
authors: G
authors: Wang
authors: Brenda J
authors: BJ
authors: Tromp
authors: Thomas A
authors: TA
authors: Puchalski
authors: Frances
authors: F
authors: Balkwill
authors: Birge
authors: B
authors: Berns
authors: Shobha
authors: S
authors: Seetharam
authors: Johann S
authors: JS
authors: de Bono
authors: Anthony W
authors: AW
authors: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000080908:Broadly Neutralizing Antibodies; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D000080908:Broadly Neutralizing Antibodies; D018932:Chemokine CCL2; C581643:carlumab