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2.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33097612

RESUMO

BACKGROUND: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. METHODS: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. RESULTS: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. CONCLUSION: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. TRIALREGISTRATION NUMBER: NCT02760797.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD40/metabolismo , Neoplasias/tratamento farmacológico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Neoplasias/imunologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo
3.
Acta Clin Belg ; 75(2): 128-135, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30609907

RESUMO

Background: Chemotherapy plays an important role in the treatment of early breast cancer (EBC). Granulocyte-colony stimulating factors (G-CSF) can reduce the risk of febrile neutropenia as primary prophylaxis (PP) or secondary prophylaxis (SP). The BRONS study investigated the incidence of serious neutropenic events (SNE) and G-CSF use in a Belgian population of EBC patients treated with myelosuppressive polychemotherapy.Methods: Conducted in 2011, this study was a prospective, multicentre, observational trial involving 260 patients. The primary endpoint was the incidence of SNE defined as either febrile neutropenia (FN) or prolonged severe neutropenia (PSN; neutrophil count ≤0.5 × 109 for at least five days). Secondary endpoints included a description of the chemotherapeutic regimens prescribed and G-CSF use.Results: Nine percent of patients were treated with a dose-dense regimen (DD) and 91% received classical chemotherapy (CC). PP with G-CSF (PPG) was given to 20% of patients (100% in DD and 11% in CC). Eighteen percent of patients presented a SNE (4% in DD and 20% in CC) of which 15% were FN and 3% PSN. SNE occurrence was 8% in the PPG subgroup and 21% in the no-PPG subgroup. In the DD subgroup, all patients received PPG and no FN was reported. Twenty six adverse events related to G-CSF were reported in 8.2% of patients and two of these were classified as severe.Conclusion: This observational study highlights the high incidence of SNE with CC regimens in patients who do not receive PPG. It also confirms the safe profile of DD regimens with G-CSF support.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Bélgica , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
4.
Future Sci OA ; 4(10): FSO341, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30457576

RESUMO

Metastatic urothelial cancer is an aggressive disease associated with a poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. After failure of platinum-based therapy and in cisplatin-ineligible patients, therapeutic options are limited. Malignant cells evolve mechanisms to evade immune recognition, including the expression of cell-surface molecules, named immune checkpoints, on tumor and tumor-specific lymphocytes. Immunotherapy, by targeting these checkpoints, represents a new tool to improve the patient outcome in advanced urothelial carcinoma (UC). Recently, the US FDA approved, in a short time, several immune checkpoint inhibitors in metastatic UC, both after failure of platinum-based therapy and in first-line setting in cisplatin-ineligible patients. This article aims to review the place of immunotherapy in advanced UC.

5.
BMJ Open ; 7(11): e017075, 2017 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-29133316

RESUMO

INTRODUCTION: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. METHODS AND ANALYSIS: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03018405, EudraCT 2016-003312-12; Pre-result.


Assuntos
Subfamília K de Receptores Semelhantes a Lectina de Células NK/administração & dosagem , Metástase Neoplásica/terapia , Neoplasias/terapia , Projetos de Pesquisa , Bélgica , Feminino , Humanos , Imunoterapia/efeitos adversos , Masculino , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/classificação , Estados Unidos
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