Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma

NCT ID: NCT03896113

Last Updated: 2020-01-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-13
• Study Completion Date: 2022-06-30

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

Conditions

Endometrium Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Celecoxib 200mg capsule

Intervention Type: DRUG

Patient confirmed with endometrial cancer will received twice daily 200 mg Celecoxib, 15 days before the surgery.

Interventions

Celecoxib 200mg capsule

Patient confirmed with endometrial cancer will received twice daily 200 mg Celecoxib, 15 days before the surgery.

Intervention Type: DRUG

Other Intervention Names

Cyclooxygenase-2 (COX-2) inhibitor

Eligibility Criteria

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.

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Benoit van den Eynde, PhD

Role: STUDY_DIRECTOR

Institut de Duve - UCL

Nicolas Van Baeren, PhD

Role: STUDY_DIRECTOR

Institut de Duve- UCL

Jean-François Baurain, PhD

Role: STUDY_CHAIR

Cliniques universitaire St-Luc

Pierre van der Bruggen, PhD

Role: STUDY_CHAIR

Institut de Duve

Locations

Cliniques Universitaires Saint Luc

Brussels, , Belgium

Site Status: RECRUITING

Gasthuisberg - KULeuven

Leuven, , Belgium

Site Status: NOT_YET_RECRUITING

Countries

Belgium

Central Contacts

Mathieu Luyckx, MD

Role: CONTACT

mathieu.luyckx@uclouvain.be

27649509 ext. +32

Jean-Luc Squifflet, PhD

Role: CONTACT

jean-luc.squifflet@uclouvain.be

27641071 ext. +32

Facility Contacts

Mathieu Luyckx, MD

Role: primary

mathieu.luyckx@uclouvain.be

+3227649509

Ignace Vergote, PhD

Role: primary

ignace.vergote@kuleuven.be

16 3 44635 ext. + 32

An Coosemans, PhD

Role: backup

an.coosemans@kuleuven.be

16 3 44635 ext. +32

References

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.

Reference Type: BACKGROUND

PMID: 28765120 (View on PubMed)

Other Identifiers

LUC19-001

Identifier Type: -

Identifier Source: org_study_id