Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma
Кључне речи
Апстрактан
Опис
Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that regulates immune responses by degrading tryptophan, which is required for efficient T-cell activation. IDO1 expression is limited in normal tissues but is induced by IFN-gamma in inflammatory tissues, to prevent excessive T-cell activity. The investigator's collaborators previously reported that IDO1 is expressed in many human tumours, and that pharmacological inhibition of IDO1 leads to immune rejection of IDO1+ mouse tumours. Based on these results, IDO1 inhibitors are now in clinical development. A first inhibitor, Epacadostat, showed encouraging results combined with anti- Programmed Cell Death -1 (PD-1) antibodies. Tumoural expression of IDO1 can be induced by IFN-gamma, which is produced by tumour-infiltrating lymphocytes (TIL), and represents a mechanism of adaptive immune resistance. However, other tumours express IDO1 in the absence of TIL and Interferon-gamma (INF gamma). This seems to be particularly frequent in endometrial carcinoma. This constitutive IDO1 expression prevents T-cell infiltration and represents a mechanism of intrinsic immune resistance. The investigator's collaborators recently showed that constitutive tumoural expression of IDO1 was triggered by cyclooxygenase-2 (COX-2) and mediated by autocrine prostaglandin-E2 (PGE2) signaling via the Protein Kinase C (PKC) and phosphoinositide 3-kinase (PI3K) pathways. Constitutive IDO1 expression was reduced by COX-2 inhibitors in vitro. Celecoxib is a well-known and widely used anti-inflammatory drug. It is a specific inhibitor of COX-2. In vivo, celecoxib induced immune rejection of IDO1-expressing human tumour xenografts, while reducing IDO1 expression and promoting T-cell infiltration. These preclinical results suggest that COX-2 inhibition in patients carrying tumours expressing IDO1 constitutively will decrease IDO1 expression, increase T-cell infiltration and might increase responsiveness to anti-PD-1/ Programmed Cell Death Ligand-1(PD-L1) therapy and thereby exert enhanced anti-tumour activity. The investigators wish to obtain clinical evidence that celecoxib can induce these first two effects
Датуми
Последња верификација: | 12/31/2019 |
Фирст Субмиттед: | 03/07/2019 |
Предвиђена пријава послата: | 03/26/2019 |
Прво објављено: | 03/28/2019 |
Послато последње ажурирање: | 01/06/2020 |
Последње ажурирање објављено: | 01/09/2020 |
Стварни датум почетка студије: | 11/12/2019 |
Процењени датум примарног завршетка: | 06/29/2022 |
Предвиђени датум завршетка студије: | 06/29/2022 |
Стање или болест
Интервенција / лечење
Drug: Celecoxib
Фаза
Групе руку
Арм | Интервенција / лечење |
---|---|
Experimental: Celecoxib Patients with confirmed primary endometrioid adenocarcinoma eligible for first line curative surgery will receive celecoxib 400 mg twice a day, for 15 days before the curative surgery for their endometrial cancer. The patients will undergo an endometrial biopsy at the inclusion and during the surgery. | Drug: Celecoxib Patient confirmed with endometrial cancer will received twice daily 200 mg Celecoxib, 15 days before the surgery. |
Критеријуми
Узраст подобан за студирање | 18 Years До 18 Years |
Полови подобни за студирање | Female |
Прихвата здраве волонтере | да |
Критеријуми | Key Inclusion Criteria: - Women > 18 years of age. - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 - Adequate renal, hepatic and haematologic functions as defined by laboratory parameters. - Agrees to undergo additional endometrial biopsies for scientific purposes. Key Exclusion Criteria: - Known hypersensitivity or intolerance to celecoxib - Active, known or suspected autoimmune disease. Vitiligo, type I diabetes mellitus, residual hypothyroidism controlled by hormone substitution therapy, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are allowed. - Positive hepatitis B or C, HIV, and pregnancy tests. - Immunosuppressive treatment |
Исход
Примарне мере исхода
1. Reduction of tumoural cells expression IDO after celecoxib treatment. If more than 10% of all the tumoural cells have a staining for IDO, the tumour is considered as IDO (+), if less than 10%. [after 15 days of celecoxib administration]
2. Modification of tumoural T Cells infiltration after the treatment with celecoxib. The number of Cluster of Differenciation (CD) 4 and CD8 T cells will be counted before and after the treatment. [after 15 days of celecoxib administration]
Секундарне мере исхода
1. Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Event Version 4.0 (CTCAE v4.0). [from the first intake of the celecoxib to one day after the surgery]