Clinical trial NCT03896113: Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma
Official title: Influence of the Celecoxib Administration Before Surgery for Endometrial Cancer on Indoleamine 2,3-dioxygenase 1 (IDO1) Tumor Expression and Immune Cells Tumor's Infiltration
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Endometrium Cancer
Lead sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Sponsor class: OTHER
First posted: 2019-03-29
Enrollment: 48
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label, proof of concept phase II study. One arm, no placebo: All the patient will received the treatment and biopsies before and after the treatment will be compared regarding Indoleamine 2,3-dioxygenase 1 (IDO-1) expression and Immune T cells infiltration of the tumour
Primary purpose: TREATMENT

Brief summary: Indoleamine 2,3 dioxygenase 1 (IDO 1) is the major enzyme catabolising the Tryptophan outside the liver. It has been shown that its plays a important role in generating a immunosuppressive micro-environment in tumors. IDO expression has been shown by Hennequart et al. to be driven by Cyclooxygenase-2 (COX-2) expression. The investigator's team also shown that anti-COX2, celecoxib, can in a xenograft models of ovarian cancer decrease IDO1 expression and result in an infiltration of the tumor by T cells. The investigator proposed then to conduct a proof of concept study to evaluate the effect of pre-operative short administration of Celecoxib on IDO expression and Immune cells tumors infiltration, in patients with endometrial cancer. Indeed, this tumor type is well known to express frequently a high level of IDO.

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: 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%.
timeFrame: after 15 days of celecoxib administration
measure: 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.
timeFrame: after 15 days of celecoxib administration
Secondary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Event Version 4.0 (CTCAE v4.0).
timeFrame: from the first intake of the celecoxib to one day after the surgery
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc
city: Leuven
country: Belgium
facility: Gasthuisberg - KULeuven
Study officials:
affiliation: Institut de Duve - UCL
name: Benoit van den Eynde, PhD
role: STUDY_DIRECTOR
affiliation: Institut de Duve- UCL
name: Nicolas Van Baeren, PhD
role: STUDY_DIRECTOR
affiliation: Cliniques universitaire St-Luc
name: Jean-François Baurain, PhD
role: STUDY_CHAIR
affiliation: Institut de Duve
name: Pierre van der Bruggen, PhD
role: STUDY_CHAIR
References:
citation: Hennequart M, Pilotte L, Cane S, Hoffmann D, Stroobant V, Plaen E, Van den Eynde BJ. Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. Cancer Immunol Res. 2017 Aug;5(8):695-709. doi: 10.1158/2326-6066.CIR-16-0400. Epub 2017 Jul 21.