Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data

Fetterly, Gerald J.; Aras, Urvi; Meholick, Patricia D.; Takimoto, Chris H.; Seetharam, Shobha; McIntosh, Thomas; Bono, Johann S. de; Sandhu, Shahneen; Tolcher, Anthony W.; Davis, Hugh M.; Zhou, Honghui; Puchalski, Thomas A.

doi:10.1002/jcph.140

Cited by 28 publications

(28 citation statements)

References 23 publications

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“…That study also showed a dose-dependent increase in total CCL2 levels (>2000 times baseline levels), although most of this was presumably complexed with anti-CCL2, as the report suggests that free levels of CCL2 were suppressed [32]. In another study of carlumab in cancer patients, free levels of CCL2 were able to be suppressed when measured shortly after infusion, but as early as 7 days later were at or above baseline levels [33]. These data suggest that there is a large pool of CCL2 available for binding to anti-CCL2 antibodies, but that suppression of free CCL2 for prolonged periods did not occur.…”

Section: Discussionmentioning

confidence: 82%

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab

et al. 2015

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The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg −1 , 5 mg·kg, or 15 mg·kg −1 ) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo −0.582%, 1 mg·kg −1 −0.533%, 5 mg·kg −1 −0.799% and 15 mg·kg −1 −0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg −1 −290 mL, 5 mg·kg −1 −370 mL and 15 mg·kg −1 −320 mL) compared with placebo (−130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg −1 group (53.1%) compared with 1 mg·kg −1 (15.2%), 15 mg·kg −1 (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted. Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients. @ERSpublications It is unlikely that carlumab provides benefit to patients with idiopathic pulmonary fibrosis

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Section: Discussionmentioning

confidence: 82%

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab

et al. 2015

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“…25 However, the therapy failed to effectively engage the desired target and pharmacokinetic data revealed a rapid dissociation of the antibody, resulting in an undesired increase in serum CCL2 concentrations. 26 In this current study, we utilized a CCR2 small molecule antagonist and it is feasible that by targeting the receptor we are able to overcome the limitations observed in these prior trials. Another potential obstacle of targeting the CCL2/CCR2 axis is illustrated by studies demonstrating that cessation of αCCL2 therapy resulted in increased pulmonary metastasis and decreased survival in a murine model of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial

Nywening

Wang‐Gillam

Sanford

et al. 2016

The Lancet Oncology

632

444

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Background Pancreatic ductal adenocarcinoma utilizes the CCL2/CCR2 chemokine axis to facilitate recruitment of tumor associated macrophages to sculpt an immunosuppressive tumor microenvironment. This pathway has prognostic implications in pancreas cancer, and blockade of CCR2 restores anti-tumor immunity in pre-clinical models. This provided the rationale for a clinical study in pancreatic adenocarcinoma to determine the safety and recommended phase 2 oral dosage of the CCR2 inhibitor PF-04136309 in combination with chemotherapy (FOLFIRINOX). Methods In this single-center, open label, phase Ib clinical trial patients age ≥ 18 years with treatment naïve borderline resectable or locally advanced, biopsy-proven pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status <2, measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1, and normal end organ function were eligible for enrollment. FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2, and bolus fluorouracil 400 mg/m2 followed by 2,400 mg/m2 46 hour continuous infusion) was administered every 2 weeks for a total of six treatment cycles. To determine the recommended phase 2 dose, PF-04136309 was orally administered at a starting dose of 500 mg twice daily in a standard 3+3 dose de-escalation design with an expansion phase planned at the recommended phase 2 dose. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 3 months. The primary endpoints were to determine the recommended phase 2 dose and toxicity of PF-04136309 in combination with FOLFIRINOX. All patients in the dose de-escalation and expansion phase received the recommended phase 2 dose of PF-04136309 were combined for assessment of treatment toxicity by an intention to treat analysis. For tissue specimen comparison in corollary studies, a group of patients receiving FOLFIRINOX alone were enrolled and evaluated for treatment related toxicity. This study has been completed and is registered at ClinicalTrials.gov; number NCT01413022. Results From April 19th, 2012 through November 12th, 2014 a total of 47 patients were enrolled. The dose de-escalation group (n=6) received PF-04136309 at 500 mg administered orally twice daily. No dose-limiting toxicities were observed and this was established as the recommended phase 2 dose. The expansion phase cohort (n=33) and patients in the dose de-escalation arm receiving PF-04136309 at the recommended phase 2 dose (n=6) were combined for assessment of treatment related toxicity. No therapy related deaths occurring during the study interval. Early termination as the result of treatment related toxicity occurred in 2 of the 39 patients (5%) in the FOLFIRINOX plus PF-04136309 arm. Grade ≥3 adverse events reported in ≥10% of the patients receiving PF-04136309 included neutropenia in 27 patients (69%), febrile neutropenia in 7 patients (18%), lymphopenia in 4 patients (10%), diarrhea in 6 patients (15%), and hypokalemia in 7 patients (18%). Among...

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“…In addition, clinical trials have reported limited to no therapeutic efficacy of the CCL2-neutralizing antibody CNTO888 either as a single agent or in combination with chemotherapy for the treatment of metastatic and nonmetastatic cancer [20], [21], [22]. Studies have suggested that a lack of efficacy was mainly due to clearance of antibody and rapid dissociation of antibody-CCL2 complex in vivo , leading to rebound of CCL2 levels during the antibody treatment [23]. The majority of studies have involved interval injections of CCL2-blocking reagents (antibody or inhibitor).…”

Section: Introductionmentioning

confidence: 99%

Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts

Yao

Smart

et al. 2017

Translational Oncology

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Chemokines are small soluble molecules that play critical roles in wound healing, infection, and cancer progression. In particular, overexpression of the C-C motif chemokine ligand 2 (CCL2) in multiple cancer types correlates with poor patient prognosis. Animal studies have shown that CCL2 signals to macrophages and breast cancer cells to promote tumor growth, invasion, and metastasis, indicating that CCL2 is a promising therapeutic target. However, the effectiveness of human-specific neutralizing antibodies has not been fully evaluated. Furthermore, controversies remain on the use of neutralizing antibodies to target CCL2 and could be due to mode of drug delivery. Here, we investigated the effects of continuous delivery of human CCL2-neutralizing antibodies on breast cancer progression. Nude mice bearing MCF10CA1d breast tumor xenografts were implanted with osmotic pumps containing control IgG or anti-CCL2 and analyzed for CCL2 levels and tumor progression over 4 weeks. Despite inhibiting CCL2-induced migration in vitro, CCL2-neutralizing antibodies did not significantly affect tumor growth, invasion, macrophage recruitment, or tumor angiogenesis. CCL2 antibodies did not affect murine CCL2 levels but significantly increased human CCL2 levels in circulating blood and tumor interstitial fluid. CCL2-neutralizing antibodies reduced CCL2 levels in cultured cells short term at high concentrations. Enzyme-linked immunosorbent assay analysis of CCL2 in cultured fibroblasts and breast cancer cells revealed that the neutralizing antibodies sequestered CCL2 in the media. CCL2 levels were restored once the antibodies were removed. These studies reveal limitations in CCL2-neutralizing antibodies as a therapeutic agent, with important implications for translating CCL2 targeting to the clinic.

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Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data

Cited by 28 publications

References 23 publications

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab

CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: a phase 2 trial of carlumab

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial

Continuous Delivery of Neutralizing Antibodies Elevate CCL2 Levels in Mice Bearing MCF10CA1d Breast Tumor Xenografts

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