Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study

Target Oncol. 2015 Mar;10(1):111-23. doi: 10.1007/s11523-014-0320-2. Epub 2014 Jun 15.

Abstract

C-C chemokine ligand 2 (CCL2) stimulates tumor growth, metastasis, and angiogenesis. Carlumab, a human IgG1κ anti-CCL2 mAb, has shown antitumor activity in preclinical and clinical trials. We conducted a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel + carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Patients had advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed. Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on docetaxel (n = 15), gemcitabine (n = 12), paclitaxel or carboplatin (n = 12), or PLD (n = 14). Total serum CCL2 concentrations increased post-treatment with carlumab alone, consistent with carlumab-CCL2 binding, and continued increase in the presence of all chemotherapy regimens. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). One partial response and 18 (38 %) stable disease responses were observed. The most common drug-related grade ≥3 adverse events were docetaxel arm-neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm-neutropenia (2/12); paclitaxel + carboplatin arm-neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm-anemia (3/14) and stomatitis (2/14). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serum CCL2 or significant tumor responses were observed.

Trial registration: ClinicalTrials.gov NCT01204996.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing / administration & dosage*
  • Antibodies, Neutralizing / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Broadly Neutralizing Antibodies
  • Carboplatin / administration & dosage
  • Carboplatin / adverse effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Docetaxel
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Doxorubicin / analogs & derivatives
  • Female
  • Gemcitabine
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / adverse effects
  • Taxoids / administration & dosage
  • Taxoids / adverse effects

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Broadly Neutralizing Antibodies
  • Taxoids
  • liposomal doxorubicin
  • Deoxycytidine
  • Docetaxel
  • Polyethylene Glycols
  • carlumab
  • Doxorubicin
  • Carboplatin
  • Paclitaxel
  • Gemcitabine

Associated data

  • ClinicalTrials.gov/NCT01204996