title: 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.
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.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Brana
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Lorrin K
authors.initials: LK
authors.lastname: Yee
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: Shobha
authors.initials: S
authors.lastname: Seetharam
authors.forename: Bob
authors.initials: B
authors.lastname: Zhong
authors.forename: Carla J
authors.initials: CJ
authors.lastname: de Boer
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000080908:Broadly Neutralizing Antibodies; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D043823:Taxoids; C506643:liposomal doxorubicin; D003841:Deoxycytidine; D000077143:Docetaxel; D011092:Polyethylene Glycols; C581643:carlumab; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel; D000093542:Gemcitabine