Brief Title
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
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
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
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%.
Secondary Outcome
Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Event Version 4.0 (CTCAE v4.0).
Condition
Endometrium Cancer
Intervention
Celecoxib 200mg capsule
Study Arms / Comparison Groups
Celecoxib
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
48
Start Date
November 13, 2019
Completion Date
June 30, 2022
Primary Completion Date
June 30, 2022
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
Gender
Female
Ages
18 Years - 99 Years
Accepts Healthy Volunteers
No
Contacts
Benoit van den Eynde, PhD, 27649509, [email protected]
Location Countries
Belgium
Location Countries
Belgium
Administrative Informations
NCT ID
NCT03896113
Organization ID
LUC19-001
Responsible Party
Sponsor
Study Sponsor
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Study Sponsor
Benoit van den Eynde, PhD, Study Director, Institut de Duve - UCL
Verification Date
January 2020