An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Tresckow, Bastian von; Morschhauser, Franck; Ribrag, Vincent; Topp, Max S.; Chien, Caly; Seetharam, Shobha; Aquino, Regina; Kotoulek, Sonja; Boer, Carla J. de; Engert, Andreas

doi:10.1158/1078-0432.ccr-14-1845

Cited by 92 publications

(87 citation statements)

References 38 publications

(50 reference statements)

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“…Another tyrosine kinase inhibitor, JNJ-40346527, was also investigated in relapsed or refractory Hodgkin lymphoma. In this phase 1/2 study, one patient out of 21 showed complete remission as best overall response and 11 patients experienced disease stabilization [7]. Both RG7155 and PLX3397 have induced comparable pharmacodynamic changes including a decrease in CD14 + CD16 + positive peripheral monocytes and an increase in systemic CSF-1, the latter being more prominent for RG7155.…”

Section: Clinical Development Of Csf-1/csf-1r Inhibitorsmentioning

confidence: 90%

“…MCS110 (US2006/029186) binds to the ligand CSF-1. Small molecules targeting the tyrosine kinase domain (ARRY-382, JNJ-40346527 [7], PLX3397 [54] and PLX7486 (for a general review on small molecule CSF-1R kinase inhibitors see [55]) do not exclusively target CSF-1R but also e.g., c-Kit, a receptor important in the development of myeloid cells making it difficult to dissect effects solely mediated by the CSF-1R pathway. (B) Agents targeting the mouse CSF-1/CSF-1R for preclinical evaluation.…”

Section: Current Opinion In Pharmacologymentioning

confidence: 99%

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CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

Ries

Hoves

Cannarile

et al. 2015

Current Opinion in Pharmacology

105

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Section: Clinical Development Of Csf-1/csf-1r Inhibitorsmentioning

confidence: 90%

Section: Current Opinion In Pharmacologymentioning

confidence: 99%

CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

Ries

Hoves

Cannarile

et al. 2015

Current Opinion in Pharmacology

105

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“…In some studies no dose-limiting toxicities (DLTs) were reported [12, 18, 25], whereas others have observed DLTs defining a maximum tolerated dose (MTD) [17, 19, 22]. Overall, the adverse event (AE) profile of CSF1R inhibitors has been characterized quite extensively for the different compounds.…”

Section: Clinical Safety and Tolerability Of Csf1r Inhibitorsmentioning

confidence: 99%

“…Frequently reported AEs for both small molecules and mAbs include fatigue, elevated liver enzymes, facial and peripheral edema, asthenia, pruritus, rash, nausea/vomiting, headache, dry skin, increased lacrimation, and decreased appetite [12, 17, 18, 22, 26–30]. Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 25–27, 30, 31]. Most studies reported that, despite elevations of these enzymes, patients did not experience clinical signs of liver toxicity, and bilirubin levels remained within the normal range [22, 27, 30, 31].…”

Section: Clinical Safety and Tolerability Of Csf1r Inhibitorsmentioning

confidence: 99%

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy

Cannarile

Weisser

Jacob

et al. 2017

j. immunotherapy cancer

735

655

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The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ-specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future.

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“…Recently, specific inflammatory markers have been singled out, such as tumor associated macrophages (TAMs), matrix metalloproteinases (MMPs), sphingosine 1-phosphate (S1P), and C-reactive protein (CRP), as well as IL6 and IL8. Importantly, novel therapies targeting TAM (CSF-1R inhibitors) are currently being tested in clinical trials for glioblastoma and Hodgkin lymphoma [24, 25]. In contrast, the role of acute inflammation within the tumor on cancer progression and metastasis has not been extensively addressed in mouse models or in human breast cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation

Szalayova

Ogrodnik

Spencer

et al. 2016

Breast Cancer Res Treat

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Background Chronic inflammation is known to facilitate cancer progression and metastasis. Less is known about the effect of acute inflammation within the tumor microenvironment, resulting from standard invasive procedures. Recent studies in mouse models have shown that the acute inflammatory response triggered by a biopsy in mammary cancer increases the frequency of distal metastases. Although tumor biopsies are part of the standard clinical practice in breast cancer diagnosis, no studies have reported their effect on inflammatory response. The objective of this study is to 1) determine whether core needle biopsies in breast cancer patients trigger an inflammatory response, 2) characterize the type of inflammatory response present, and 3) evaluate the potential effect of any acute inflammatory response on residual tumor cells. Methods The biopsy wound site was identified in the primary tumor resection tissue samples from breast cancer patients. The inflammatory response in areas adjacent (i.e. immediately around previous biopsy site) and distant to the wound biopsy was investigated by histology and immunohistochemistry analysis. Proliferation of tumor cells was also assayed. Results We demonstrate that diagnostic core needle biopsies trigger a selective recruitment of inflammatory cells at the site of the biopsy and they persist for extended periods of time. While macrophages were part of the inflammatory response, an unexpected accumulation of eosinophils at the edge of the biopsy wound was also identified. Importantly, we show that biopsy causes an increase in the proliferation rate of tumor cells located in the area adjacent to the biopsy wound. Conclusions Diagnostic core needle biopsies in breast cancer patients do induce a unique acute inflammatory response within the tumor microenvironment and have an effect on the surrounding tumor cells. Therefore biopsy-induced inflammation could have an impact on residual tumor cell progression and/or metastasis in human breast cancer. These findings may carry relevance in the clinical management of breast cancer.

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An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Cited by 92 publications

References 38 publications

CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy

Human breast cancer biopsies induce eosinophil recruitment and enhance adjacent cancer cell proliferation

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