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 (original) (raw)

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.

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Acknowledgments

Gianna Paone and Jennifer Han of Janssen Scientific Affairs, LLC, provided assistance with writing, editing, preparing, and submitting this manuscript. Janssen Research & Development, LLC, provided funding for the study. This trial was registered at ClinicalTrials.gov, NCT01204996.

Conflict of interest

Drs. Puchalski, Seetharam, Zhong, and de Boer are employees of Janssen, own stock in Johnson & Johnson, and/or are currently conducting research sponsored by Janssen. Antonio Calles is a Rio Hortega fellowship grant recipient from the Instituto de Salud Carlos III (CM09/00283). All remaining authors have declared no conflicts of interest.

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Author notes

  1. Lorrin K. Yee
    Present address: Vista Oncology, 141 Lilly Road NE, Olympia, WA, 98502, USA

Authors and Affiliations

  1. Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Spain
    Irene Brana & Josep Tabernero
  2. START Madrid, Centro Integral Oncológico Clara Campal, Calle Oña, 10, 28050, Madrid, Spain
    Antonio Calles & Emiliano Calvo
  3. Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro, 3, 28029, Madrid, Spain
    Antonio Calles
  4. Karmanos Cancer Institute, Wayne State University, 4100 John R Street, Detroit, MI, 48201, USA
    Patricia M. LoRusso
  5. Northwest Medical Specialties, 1624 South I Street, Suite #305, Tacoma, WA, 98405, USA
    Lorrin K. Yee
  6. Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA, 19477, USA
    Thomas A. Puchalski, Shobha Seetharam & Bob Zhong
  7. Janssen Biologics, BV, Einsteinweg 92, 2333 CD, Leiden, The Netherlands
    Carla J. de Boer

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  1. Irene Brana
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Correspondence toCarla J. de Boer.

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Brana, I., Calles, A., LoRusso, P.M. et al. 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.Targ Oncol 10, 111–123 (2015). https://doi.org/10.1007/s11523-014-0320-2

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