Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types.
BMJ Open
; 7(11): e017075, 2017 Nov 12.
Article
em En
| MEDLINE
| ID: mdl-29133316
ABSTRACT
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 ANDANALYSIS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Projetos de Pesquisa
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Subfamília K de Receptores Semelhantes a Lectina de Células NK
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Metástase Neoplásica
/
Neoplasias
Tipo de estudo:
Clinical_trials
/
Guideline
/
Prognostic_studies
Limite:
Female
/
Humans
/
Male
País/Região como assunto:
America do norte
/
Europa
Idioma:
En
Revista:
BMJ Open
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Bélgica