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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

(2017) BMJ OPEN. 7(11).
Author
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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 CD3 zeta 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: 3x10(8), 1x10(9) and 3x10(9) 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.
Keywords
RECEPTOR T-CELLS, CHIMERIC NKG2D RECEPTOR, SOLID TUMORS, OVARIAN-CANCER, B-CELL, ADOPTIVE IMMUNOTHERAPY, ANTITUMOR-ACTIVITY, ANTIGEN RECEPTORS, THERAPY, RESPONSES

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Citation

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Chicago
Lonez, Caroline, Bikash Verma, Alain Hendlisz, Philippe Aftimos, Ahmad Awada, Eric Van den Neste, Gaetan Catala, et al. 2017. “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).
APA
Lonez, C., Verma, B., Hendlisz, A., Aftimos, P., Awada, A., Van den Neste, E., Catala, G., et al. (2017). 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).
Vancouver
1.
Lonez C, Verma B, Hendlisz A, Aftimos P, Awada A, Van den Neste E, et al. 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. 2017;7(11).
MLA
Lonez, Caroline, Bikash Verma, Alain Hendlisz, et al. “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 (2017): n. pag. Print.
@article{8563270,
  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 CD3 zeta 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: 3x10(8), 1x10(9) and 3x10(9) 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.},
  articleno    = {e017075},
  author       = {Lonez, Caroline and Verma, Bikash and Hendlisz, Alain and Aftimos, Philippe and Awada, Ahmad and Van den Neste, Eric and Catala, Gaetan and Machiels, Jean-Pascal H and Piette, Fanny and Brayer, Jason B and Sallman, David A and Kerre, Tessa and Odunsi, Kunle and Davila, Marco L and Gilham, David E and Lehmann, Frederic F},
  issn         = {2044-6055},
  journal      = {BMJ OPEN},
  language     = {eng},
  number       = {11},
  pages        = {14},
  title        = {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},
  url          = {http://dx.doi.org/10.1136/bmjopen-2017-017075},
  volume       = {7},
  year         = {2017},
}

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