Determine Whether Administering Celecoxib During Radiotherapy Can Reduce the Risk of Recurrence of Triple-negative Breast Cancer. Pilot Study
Phase: PHASE2
Conditions: Triple-Negative Breast Cancer
Sponsor: Université de Sherbrooke

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Determine whether administering celecoxib during radiotherapy can reduce the 
risk of recurrence of triple-negative breast cancer. Pilot study 
 
Trial acronym: Triple negative breast cancer and celecoxib 
 
Protocol number:     TNBC2025-5681 
 
Version: July 2025 
 
Investigational Product Name: Celecoxib (MAR-CELECOXIB) 
 
Promoter : Benoit Paquette, Ph.D. 
Department of Medical Imaging and Radiation 
Sciences Faculty of Medicine and of Health Sciences 
Université de Sherbrooke 
3001, 12th Avenue North, Sherbrooke, Québec, 
Canada J1H 5N4 
 
 
Clinical phase: 2 
 
Short title: Triple negative breast cancer and celecoxib 
 
Drug manufacturer name and address: Marcan Pharmaceuticals Inc. 
2 Gurdwara Road, Suite 112 
Ottawa, Ontario 
      K2E 1A2 Canada 
 
The trial will be conducted in accordance with Good Clinical Practice and applicable regulatory 
requirements of the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH E6(R2)) 

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PROTOCOL SUMMARY 
1.1 Protocol Synopsis 
1.1.1 Primary and Secondary Objectives and Estimantes 
Relapses occur in 20 to 30% of patients with early-stage triple-negative breast cancer (TNBC), which 
is characterized by the absence of three receptors: the estrogen receptor (ER), progesterone receptor 
(PR) and human epidermal growth factor receptor 2 (HER-2). Radiotherapy (RT) can increase or 
decrease, depending on the patient, the level of cytokines that promote metastasis development. To help 
prevent the development of metastasis, the cyclooxygenase-2 (COX-2) inhibitor celecoxib will be 
administered during RT. This treatment aims to prevent RT-induced cytokine increases and, ultimately, 
improve patient prognosis. 
 
The primary objective of this pilot study is to assess the feasibility of recruiting participants and 
implementing the study steps, with the intention of conducting a large-scale study in the future. The 
secondary objective is to evaluate celecoxib ability to inhibit the RT-induced stimulation of 
cytokines associated with metastasis development. This will be assessed by comparing the levels 
of these cytokines in plasma samples collected before, during, and after RT. In the exploratory 
objective, TNBC cells will be incubated in vitro with these plasma samples to determine whether 
administering celecoxib during RT can prevent increased cancer cell invasion and metastasis formation 
in mice.  
 
1.1.2 Overall Design 
 
Intervention: 
Celecoxib (MAR-CELECOXIB) 
Control number: 270498 
Population Type: 
Women with early-stage TNBC 
Intervention Model: 
One capsule of 100 mg celecoxib or placebo will 
be taken after breakfast and one after supper, 
starting 7 days before RT and ending 14 days after 
RT. 
 
Population Diagnosis or Condition: 
Participants with pathology-confirmed TNBC 
status, primary tumor removed by breast- 
conserving surgery and negative margins, regional 
lymph node of pN0 to pN3, and no evidence of 
distant metastasis at diagnosis. Participants will 
receive neoadjuvant chemotherapy. RT will be 
given 
after 
surgery. 
Immunotherapy 
(Pembrolizumab) will be administrated according 
to the clinical standard. 
Control Type: 
Double-blind randomized clinical study 
Population Age: 
18 years and older 
Control Description: 
Control participants will take a placebo instead of 
celecoxib. 
Site Distribution and Geographic Scope: 
Centre intégré universitaire de santé et de services 
sociaux (CIUSSS) de l’Estrie – Centre hospitalier 
universitaire de Sherbrooke, Québec, Canada 

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Intervention Assignment Method: 
Participants will be recruited and followed at our 
facility, CIUSSS de l'Estrie CHUS Sherbrooke, by 
Dr. Sawyna Provencher (radiation oncologist), Dr. 
Isabelle Gauthier (radiation oncologist) and Dr. 
Michel Pavic (oncologist). 
Research assistant Hélène Therriault will give the 
participants the celecoxib or placebo bottle, 
explain the dosage to follow, and give them the 
follow-up logbook in which they will record the 
celecoxib or placebo intake, and any discomfort 
experienced, such as rashes, headaches, or 
dizziness. She will coordinate blood sampling with 
the research nurse based on administering 
celecoxib or placebo and radiotherapy sessions. 
Master Protocol: 
Determine if celecoxib taken during RT reduces 
cancer relapse. The primary objective of this pilot 
study is to assess the feasibility of recruiting 
participants and implementing the study steps. 
Drug/Device Combination Product Indicator: 
Chemotherapy and Pembrolizumab treatments 
will be administered according to clinical 
standards. The tumor will be removed by 
conservative surgery 4 to 8 weeks after the end 
of chemotherapy. RT will begin 8 to 12 weeks 
after surgery, which will allow the chemotherapy 
agents to be eliminated from the participants 
before taking celecoxib.  
Adaptive Trial Design: 
Participants who experience discomfort or an 
adverse effect as mentioned in section 4.3 will be 
withdrawn from the clinic trial. Participants 
withdrawn from the trial will continue their 
treatment as planned. 

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Number of Arms: 2 
Trial Blind Schema: 
 
 
 
Blinded Roles: The promoter, Pr Benoit Paquette, will perform randomization and inform his 
research assistant, Hélène Therriault. If any adverse effects occur, clinicians Dr. Sawyna 
Provencher (radiation oncologist), Dr. Isabelle Gauthier (radiation oncologist) and Dr. Michel Pavic 
(oncologist) will be informed if the participant has taken celecoxib. 
 
Number of Participants: Two groups containing 15 participants each. Total: 30 
 
Duration: Total planned duration of trial intervention for each participant. 
Participant recruitment will end in June 2027, with a 5-year follow-up period until 2032. 
 
Committees: The Research Ethics Committee of the CIUSSS de l'Estrie - CHUS is responsible for 
auditing the research project. 
 
 
1.2 Trial Schema 
 
 
 

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1.3 Schedule of Activities 
 
 
 
2 INTRODUCTION 
2.1 Purpose of Trial 
Breast cancer is a heterogeneous disease, encompassing a number of distinct biological entities 
associated with specific morphological and clinical behavior. TNBC is a subgroup that accounts for 
10–20% of all breast carcinomas, which is characterized by the absence of ER, PR and HER-2.1 
Hormone receptor-positive and HER2-positive breast cancers generally respond well to chemotherapy 
and targeted therapies for ER or HER2. In contrast, TNBC shows mixed results, and it does not benefit 
from targeted therapies. 
 
For some non-metastatic patients with TNBC, the prognosis is less favorable compared to other 
breast cancer subtypes, with recurrence occurring on average 2.6 years after treatment.2,3 However, 
five years after diagnosis, in patients whose cancer has not recurred early, the probability of 
recurrence is not significantly different from that of non-TNBC patients.2,4 Therefore, TNBC patients 
can be divided into two groups: those who respond well to treatment and those for whom early 
recurrence is observed.2 
 
Microfoci of cancer cells are often scattered in the breast and may be present up to a few centimeters 
from the edge of the primary tumor.5 Conservative surgery removes the primary tumor, while 
microfoci of cancer cells are targeted with RT. The treated area frequently covers the entire breast and 
the axillary and subclavian lymph nodes. Unfortunately, the radiation dose used clinically does not 
always eliminate all cancer cells spread throughout the breast, as it is intended to optimize long-
term results with minimal adverse effects. Nevertheless, many cancer cells are effectively eliminated, 
since RT reduces the likelihood of local recurrence and distant metastases.3 
 
RT induces inflammation of varying intensity in all patients. Significant skin inflammation resembling 
sunburn (dermatitis) may be observed in some women in the treated area. Rarely is this dermatitis 
accompanied by severe pain, requiring treatment to be stopped. 
 
A growing body of research suggests that radiation-induced inflammatory cytokines may stimulate 
the development of new metastases.6-13 In support of clinical observations, it has been demonstrated 
in a murine model that pre-irradiation of the mammary gland before implantation of TNBC D2A1 
cells stimulated their migration, increased the number of circulating tumor cells, and promoted the 

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development of lung metastases.6 A similar stimulation of metastasis development was also observed 
after irradiation of a D2A1 tumor implanted in the mouse mammary gland.14 The inflammatory 
pathways involved remain to be studied in detail. However, these adverse effects of radiation have 
been associated with cytokines, including interleukin-6 (IL-6) and the inflammatory enzyme COX-2. 
 
Our team is currently conducting a study in TNBC patients with the aim of developing a test based 
on an RT-induced cytokine signature to identify participants at high risk of recurrence (Project 
Title: Prediction of Radiotherapy Efficacy in Patients with Triple-Negative Breast Cancer. Project 
Number: 14-205). The preliminary results support our research hypothesis. In 23% of participants, 
plasma isolated during RT increased the invasive capacity of TNBC cells and the formation of lung 
metastases in a mouse model. This percentage corresponds to that of patients whose cancer recurred. 
The addition of a COX-2 inhibitor, celecoxib, completely blocked these adverse effects of RT. 
 
Two of the twenty TNBC participants recruited so far took a COX-2 inhibitor, including celecoxib, 
during their RT treatment for another medical indication. Unlike the other TNBC participants, the 
levels of almost all cytokines in their plasma collected during RT were decreased. Their plasma collected 
during RT did not increase the invasiveness of TNBC cells in vitro, nor the formation of metastasis in 
mice, and the cancer of these participants did not recur. This fortuitous observation suggests that 
administering celecoxib during RT could reduce the risk of recurrence in TNBC patients. This 
hypothesis will be tested in the current clinical study. 
 
2.2 Assessment of Risks and Benefits 
2.2.1 Risk Summary and Mitigation Strategy 
Celecoxib can lead to gastric toxicity when administered concomitantly with chemotherapy.15 For 
this reason, it is not typically prescribed to cancer patients. Our study addresses this issue by 
implementing a treatment plan that begins with chemotherapy, followed by tumor removal through 
surgery 4 to 8 weeks later. RT is then administered 3 to 8 weeks after the surgery. This approach 
allows for the clearance of chemotherapy agents from the body before starting celecoxib, thereby 
reducing the risk of gastric toxicity. 
 
The risk of serious adverse effects (myocardial infarction and stroke) will be minimized since 
celecoxib will be administered for a short period (26 to 40 days according to the radiotherapy plan) 
and at a dose not exceeding 200 mg/day. Nevertheless, attention will be paid to the possible serious 
adverse effects. 
 
2.2.2 Benefit Summary 
A meta-analysis showed that administration of aspirin, a cyclooxygenase (COX) inhibitor, was 
associated with a 23% reduction in the risk of breast cancer,16 a reduction that depended on the 
frequency of administration.17-19 On the other hand, it is also suggested that the lack of association 
between aspirin use and breast cancer risk, reported in other studies, may be due to too low a dose 
and too short a duration of use.20 Better protection against breast cancer risk may be achieved with 
selective COX-2 inhibitors such as celecoxib, when used regularly.21-23 
 
Similar benefits were observed regardless of ER, PR, and HER-2 expression when aspirin was 
used throughout adult life.24 A 41% risk reduction was observed for luminal A breast cancer and a 
similar 48% risk reduction for TNBC.24 These results are consistent with most studies, except for a 
few.25,26 
 

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In standard neoadjuvant therapy, celecoxib may improve the objective response rate, but not the 
pathological complete response;27,28 while its combination with adjuvant therapy may prolong 
overall survival.29 One study demonstrated that celecoxib used as maintenance therapy in patients 
with non- metastatic TNBC after adjuvant therapy prolonged disease-free survival (DFS). A 4-year 
DFS rate of 66% was measured for patients who received celecoxib compared to 41.9% for those 
who did not.30 It should be noted that this protective effect of celecoxib was not observed in 
hormone receptor-positive breast cancers, which already have a better prognosis than TNBC.29 A 
statistically significant reduction in breast cancer recurrence was also associated with regular ibuprofen 
use, but not with aspirin use.31 This reduction 
may be attributed to the suppression of the 
inflammatory process that can trigger the development of 
metastases.32 Nonsteroidal anti-
inflammatory drug (NSAID) use has also been shown to reduce the incidence of gynecological 
cancer secondary to breast cancer treatments.33 Although encouraging, these benefits of using an 
NSAID or a specific COX-2 inhibitor need to be further validated by additional studies. 
 
Regarding combining celecoxib with RT, animal models have demonstrated that this combination 
leads to better control of tumor growth.34 In clinical settings, few studies have been conducted.35 A 
phase I study showed that this combination is well tolerated and reduces itching and pain during 
RT.36 
 
2.2.3 Overall Risk-Benefit Assessment 
The risk of severe adverse effects is considered very low because celecoxib will be administered at a 
daily dose of 200 mg for only 26 to 40 days according to the radiotherapy plan. On the other 
hand, treating participants with this COX-2 inhibitor could help reduce the relapse rate of TNBC by 
preventing RT stimulation of cytokines associated with the development of metastases. 
 
3 TRIAL OBJECTIVES AND ASSOCIATED ESTIMANDS 
3.1 Primary Objective and Associated Estimands 
3.1.1 Primary Objective 
 
The primary objective of this pilot study is to assess the feasibility of recruiting participants and 
implementing the study steps, with the intention of conducting a large-scale study in the future.  
Estimand Characteristic 
Description 
 
Population 
 
Non-metastatic TNBC participants 
• Gender: Female 
• Age: 18 years or older 
• cT stage: Early 
• TNBC status confirmed by pathology 
• Regional lymph node pN0 to pN3 
• No evidence of distant metastasis 
• Primary tumor removed by conservative surgery 
with negative margins 
 
Treatment 
 
Celecoxib or placebo administration 
Capsules of 100 mg celecoxib or placebo will take per 

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3.2 Secondary Objective and Associated Estimands 
3.2.1 Secondary Objective 
The secondary objective is to determine whether taking celecoxib will prevent the increase in 
cytokines induced by RT, some of which are known to stimulate the invasion capacity of 
cancer cells and the formation of metastases. 
 
Estimand Characteristic 
Description 
Population 
Non-metastatic TNBC participants 
• Gender: Female 
• Age: 18 years or older 
• cT stage: Early 
• TNBC status confirmed by pathology 
• Regional lymph node pN0 to pN3 
• No evidence of distant metastasis 
• Primary tumor removed by conservative 
surgery with negative margins 
os one after breakfast and one after supper starting 7 
days before RT and end 14 days after RT. 
 
Chemotherapy according to the clinical standard 
(Doxorubicin, 
Cyclophosphamide, 
Paclitaxel, 
Carboplatin) 
 
Immunotherapy 
with 
Pembrolizumab 
will 
be 
administered during chemotherapy and radiotherapy 
if the tumor diameter exceeds 2 cm or if lymph nodes 
are positive. 
 
RT will consist of 26 Gy in 5 fractions or 40 Gy in 15 
fractions if participants are under 50 years old with 
lymph node positivity. 
 
Endpoint 
 
 
Feasibility of recruiting participants and 
implementing the study steps 
Confirm the ability to recruit all participants. Access 
to data sources to obtain clinical data related to the 
diagnosis, treatment, and follow-up of TNBC. 
Coordinate blood sampling by research nurses with 
radiotherapy treatment, as well as with the CRCHUS 
pharmacy to obtain vials of celecoxib or placebo. 
Establish effective communication between clinicians 
and the sponsor to facilitate participant recruitment 
and monitor adverse events. Confirm that all forms 
are completed and signed (information and consent 
form, confirmation that participants meet the 
inclusion and exclusion criteria, confirmation of each 
blood draw). 

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Treatment 
Celecoxib administration 
Capsules of 100 mg celecoxib or placebo will 
take per os one after breakfast and one after 
supper starting 7 days before RT and end 14 
days after RT. 
 
Chemotherapy according to the clinical 
standard (Doxorubicin, Cyclophosphamide, 
Paclitaxel, Carboplatin) 
Immunotherapy with Pembrolizumab will be 
administered if the tumor diameter exceeds 2 
cm or if lymph nodes are positive. 
Endpoint 
Quantification of cytokines in 
plasmas collected from TNBC 
participants 
Quantify and compare the level of 48 cytokines 
in 
plasma 
samples 
collected 
from 
30 
participants at 4 times: 1) The day before the 
start of taking celecoxib or placebo, which 
corresponds to 7 days before starting RT, 2) the 
day of the start of RT and just before 
administering the 1st fraction of radiation, 3) 
after the 4th fraction of radiation, and 4) 14 days 
after the end of RT and stopping taking 
celecoxib or placebo. 
 
3.3 Exploratory Objectives 
3.3.1 Exploratory Objectives 
As determined in preclinical models, RT can enhance the level of cytokines known to increase 
cancer cell invasion and the development of metastases. The exploratory objective will determine 
whether these adverse effects would be prevented by the administration of celecoxib during RT. 
 
Estimand Characteristic 
Description 
Population 
Non-metastatic TNBC participants 
• Gender: Female 
• Age: 18 years or older 
• cT stage: Early 
• TNBC status confirmed by pathology 
• Regional lymph node pN0 to pN3 
• No evidence of distant metastasis 
• Primary tumor removed by conservative 
surgery with negative margins 

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   Treatment 
Celecoxib administration 
Capsules of 100 mg celecoxib or placebo will 
take per os one after breakfast and one after 
supper starting 7 days before RT and end 14 
days after RT 
 
Chemotherapy according to the clinical 
standard (Doxorubicin, Cyclophosphamide, 
Paclitaxel, Carboplatin) 
Immunotherapy with Pembrolizumab will be 
administered if the tumor diameter exceeds 2 
cm or if lymph nodes are positive 
Endpoint 
Determine whether administration of 
celecoxib during RT reduces radiation- 
stimulation of cancer cell invasion and 
metastasis development in mice 
Plasma samples will be collected from 30 
participants at 4 times: 1) The day before the start 
of taking celecoxib or placebo, which corresponds 
to 7 days before starting RT, 2) the day of the start 
of RT and just before administering the 1st 
fraction of radiation, 3) after the 4th fraction of 
radiation, and 4) 14 days after the end of RT and 
stopping taking celecoxib or placebo. 
Comparison of the four plasma samples collected 
from each participant. 
Three TNBC cell lines will be incubated with the 
plasma collected from the participants. 
Following this incubation, the invasive capacity 
of the TNBC cells will be measured in vitro using 
invasion chambers. 
These cells will also be injected intravenously into 
the tail of immunocompetent mice, and the 
number of lung metastases will be determined 28 
days later. 

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4 TRIAL DESIGN 
4.1 Description of Trial Design 
Non-metastatic TNBC participants will be recruited. The overall aim is to determine whether 
administering celecoxib during RT could reduce the risk of cancer recurrence. The hypothesis is that 
celecoxib will block the increase in cytokines, induced by RT, that are known to promote cancer cell 
invasion and metastasis. The primary objective of this pilot study is to assess the feasibility of recruiting 
participants and implementing the study steps, with the intention of conducting a large-scale study in 
the future. 
 
Thirty participants will be recruited and randomized: fifteen will receive celecoxib, and fifteen will 
receive a placebo. Participants who take a COX-2 inhibitor for other medical indications or 
medications such as ibuprofen will be excluded. A limitation of this study will be the use of anti-
inflammatory drugs in the years after treatment. 
 
After chemotherapy and removal of the tumor by partial mastectomy, participants will be recruited 
by their treating physician, either the hemato-oncologist or the radiation oncologist. The pharmacy 
department of CIUSSS de l'Estrie CHUS, Sherbrooke, Quebec will prepare bottles containing 100 
capsules of 100 mg celecoxib. Bottles of placebo will be supplied by GALENOVA INC, Saint-
Hyacinthe, Quebec, Canada. Participants will take one capsule after breakfast and one after supper 
starting 7 days before RT and end 14 days after RT. RT will consist of 26 Gy in 5 fractions or 40 Gy 
in 15 fractions if participants are under 50 years old with lymph node positivity. According to the RT 
plan, celecoxib will be taken for no longer than 40 days. In a logbook, participants will report when 
celecoxib was taken and if they experience discomfort such as skin rashes, headache, or dizziness. 
See section 7 for details regarding the criteria to withdraw participants from the study. Participant 
follow-up will last 5 years after treatment and will be carried out according to clinical guidelines, 
which consist of a clinical examination and a mammogram every year. If breast density is categorized 
as D (extremely dense), an MRI will be performed in alternating years with the mammogram. A CT or 
PET scan will be conducted if symptoms such as bone pain are present. The date corresponding to the 
detection of a local or distant recurrence will be recorded in the participant file to determine whether 
taking celecoxib could reduce the risk of regional or distant recurrence. 
 
The secondary objective is to determine whether taking celecoxib will prevent the increase in 
cytokines induced by RT, some of which are known to stimulate the invasion capacity of cancer 
cells and the formation of metastases. This will be determined by collecting plasma samples at four 
time points: 1) the day before the start of taking celecoxib or placebo, which corresponds to 7 days 
before starting RT, 2) the day of the start of RT and just before administering the 1st fraction of 
radiation, 3) after the 4th fraction of radiation, and 4) 14 days after the end of RT and stopping taking 
celecoxib or placebo. During the blood draw, participants will be questioned by the research nurse to 
ensure that celecoxib is well tolerated. The impact of celecoxib on changes in 48 cytokines will be 
determined by Eve Technologies (Calgary) using laser bead multiplexing. 
 
The beneficial effect of celecoxib in preventing RT-induced cytokine elevations on cancer cell 
invasion capacity and metastasis development will be evaluated in preclinical models. This exploratory 
objective will be assessed by comparing the four plasma samples collected from each participant. Three 
TNBC cell lines will be incubated with these plasma samples. Using invasion chambers, the 
correlation between celecoxib-induced cytokine reduction and inhibition of RT-induced cancer cell 
invasion stimulation will be determined. These cells will also be injected intravenously into the tail of 
immunocompetent mice, and 28 days later, the reduction in the number of lung metastases with plasma 

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collected from participants treated with celecoxib compared to those taking placebo will be determined.   
 
4.2 Overall Rationale for Trial Design 
The relapse rate of patients with TNBC ranges between 20 and 30%. The primary objective of this 
pilot study is to assess the feasibility of recruiting participants and implementing the study steps, with 
the intention of conducting a large-scale study in the future. 
 
The increase in cytokines known to promote cancer cell invasion and metastasis by RT suggests 
that preventing this stimulation may improve the prognosis of patients with TNBC. This working 
hypothesis will be tested by determining whether celecoxib administration can block the increase of 
cytokines in plasma, compared to plasma collected from participants taking a placebo. Furthermore, 
identifying the cytokines whose levels do not increase when treating with celecoxib treatment could 
be utilized in future studies to evaluate the response of TNBC patients to celecoxib. 
 
Assays using in vitro invasion chambers and the development of lung metastases in mice will 
contribute to demonstrating that blocking RT-stimulation of protumor cytokines can attenuate two 
critical steps in cancer progression: the invasiveness of cancer cells and their ability to metastasize. 
 
4.3 Trial Stopping Rules 
Participants who experience discomfort, such as rashes, headaches, or dizziness while taking 
celecoxib, should inform the research assistant or research nurse assigned to the clinical trial. They 
will then notify the promoter, Benoit Paquette, within 24 hours, who will discuss the reported 
event with co-investigators Dr Michel Pavic (chemotherapy), Dr Sawyna Provencher (RT) and Isabelle 
Gauthier (RT). Based on the severity of the adverse effects, they will decide whether or not to withdraw 
the participant from the trial. 
 
In the event of withdrawal from the trial, the adverse effects and their severity will be compiled, 
and the serious unexpected adverse drug reactions will be reported to the Canadian Minister of Health 
and included in the scientific publications documenting the trial results. 
 
Participants withdrawn from the trial will continue their RT as planned. 
 
Annual medical follow-ups of participants will be conducted over the five years following treatment. 
 
4.4 Start of Trial and End of Trial 
The trial will start when the first participant signs the consent form (expected in August 2025) and end 
after the last participant 5-year follow-up. 
 
5 TRIAL POPULATION 
 
5.1 Description of Trial Population and Rationale 
Women aged over 18 years with pathologically confirmed TNBC breast cancer. 
 
5.2 Inclusion Criteria 
 

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• Gender: Female 
• Age: 18 years or older 
• pT stage: Early 
• TNBC status confirmed by pathology 
• Regional lymph node pN0 to pN3 
• No evidence of distant metastasis 
• Primary tumor removed by conservative surgery with negative margins 
 
5.3 Exclusion Criteria 
Participants will be excluded if they have experienced any of the following conditions in the last 
six months: 
• Stomach ulcer 
• Kidney disease: Glomerular filtration rate (GFR) lower than 50 mL/min 
• Liver disease: AST/ALT - 3 times the upper limit of normal, Bilirubine - 2 times the 
upper limit of normal, INR - 1.3 times the upper limit of normal, Cirrhose Child-Pugh B 
or more 
• Congestive heart failure: Left ventricular ejection fraction (LVEF) lower than 50% 
Participants taking an NSAID for another medical condition or as needed before starting 
their radiotherapy treatment 
Participants who have demonstrated: 
• Hypersensitivity to celecoxib 
• A history of allergic reactions to sulfonamides 
• A history of asthma attacks, urticaria, or allergic reactions after taking acetylsalicylic 
acid (ASA) or another nonsteroidal anti-inflammatory drug 
• The presence of inflammatory bowel disease 
• Proven hyperkalemia 
 
6 TRIAL INTERVENTION AND CONCOMITANT THERAPY 
6.1 Description of Investigational Trial Intervention 

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6.2 Rationale for Investigational Trial Intervention Dose and Regimen 
One capsule of 100 mg celecoxib or placebo will be taken after breakfast and one after supper, starting 
7 days before RT and ending 14 days after RT. The risk of serious side effects (myocardial infarction 
and stroke) will be minimized since celecoxib will be administered for a short period (40 days or less) 
and at a dose not exceeding 200 mg/day. 
 
6.3 Investigational Trial Intervention Administration 
One capsule of 100 mg celecoxib or placebo will be taken after breakfast and one after supper, starting 
7 days before RT and ending 14 days after RT. 
 
6.4 Investigational Trial Intervention Dose Modification 
No change in celecoxib dosage 
 
6.5 Management of Investigational Trial Intervention Overdose 
The research assistant will give the participants the celecoxib or placebo bottle, explain the dosage 
to follow, and give them the follow-up logbook in which they will record the celecoxib or placebo 
intake, and any discomfort experienced, such as rashes, headaches, or dizziness. During the four 
participant visits corresponding to the blood sampling, the research assistant will confirm with 
participants that the intake of celecoxib or placebo is respected. 
 
6.6 Preparation, Storage, Handling and Accountability of Investigational 
Trial Intervention 
6.6.1 Preparation of Investigational Trial Intervention 
The pharmacy department of CIUSSS de l'Estrie CHUS, Sherbrooke, Quebec will prepare bottles 
containing 100 capsules of 100 mg celecoxib. Bottles of placebo will be supplied by GALENOVA 
INC, Saint-Hyacinthe, Quebec, Canada. 
 
6.6.2 Storage and Handling of Investigational Trial Intervention 
The pharmacy department of CIUSSS de l'Estrie CHUS, Sherbrooke, Quebec, will store and handle 
the bottles of celecoxib. The research assistant will handle the placebo bottles and store them in a 
locked cabinet in the laboratory of the promoter, Pr Benoit Paquette. 
 
6.6.3 Accountability of Investigational Trial Intervention 
Dr. Sawyna Provencher (radiation oncologist), Dr. Isabelle Gauthier (radiation oncologist) and Dr. 
Michel Pavic (oncologist) will recruit participants. They will fill a request form addressed to Julie 
Leblond of the pharmacy department of CIUSSS de l'Estrie CHUS, asking to prepare a bottle of 
celecoxib or placebo capsules. The bottle will be identified with a code associated with each 
participant. The unused capsules of celecoxib or placebo will be brought back to the pharmacy 
department. The promoter, Pr Benoit Paquette, will randomize the participants in the arm of celecoxib 
or placebo, and inform Julie Leblond, who is responsible for the pharmacy department. 
 
6.7 Investigational Trial Intervention Assignment, Randomisation and Blinding 
6.7.1 Participant Assignment to Investigational Trial Intervention 

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Dr. Sawyna Provencher (radiation oncologist), Dr. Isabelle Gauthier (radiation oncologist) and Dr. 
Michel Pavic (oncologist) will recruit participants and validate the inclusion and exclusion criteria. 
Participants will be divided into two arms: 1) celecoxib, and 2) placebo. For this pilot study, 15 
participants per arm will be enrolled. The promoter, Pr Benoit Paquette, will randomize the participants. 
The research assistant will register the participants in an Excel file that will include participant 
characteristics (age, tumor diameter, stage, chemotherapeutic agents, chronology of the treatment 
plan – chemotherapy, surgery, RT plan – , cancer staging and grading, conservative surgery, 
pembrolizumab, Ki67, BRCA1 and 2 statuses, radiodermatitis, date of relapse). The researcher 
assistant will assign each participant a unique code beginning with "C" followed 
by a number 
indicating the chronological order of enrollment in the study. Only the research assistant and the 
promoter will know the link between the code and the patient identity. 
 
6.7.2 Randomization 
The first participant recruited will be included in the first arm, the second participant in the second 
arm, and so on. The process will begin again with the fifth and subsequent participants recruited. 
 
6.7.3 Measures to Maintain Blinding 
The promoter, Pr Benoit Paquette, will randomize the participants. Only him and the research assistant 
will know the link between participants and their identification code. 
 
6.7.4 Emergency Unblinding at the Site 
Participants who experience discomfort, such as rashes, headaches, or dizziness while taking 
celecoxib, should inform the research assistant or research nurse assigned to the clinical trial. They 
will then notify the promoter, Benoit Paquette, within 24 hours, who will discuss the reported event 
with co-investigators Dr Michel Pavic, Dr Sawyna Provencher and Dr Isabelle Gauthier. The promoter 
will inform them of the meaning of the participant identification code to ensure appropriate clinical 
follow-up. Based on the severity of the adverse effect, they will decide whether or not to withdraw 
the participant from the trial. 
 
6.8 Investigational Trial Intervention Adherence 
During the four visits of the participants corresponding to the blood sampling, the research assistant 
will confirm with them that the taking of celecoxib or placebo is respected, and that the follow-up 
book is correctly completed. 
 
6.9 Description of Noninvestigational Trial Intervention 
Chemotherapy: Doxorubicine, Cyclophosphamide, Paclitaxel, Carboplatin 
Conservative surgery 
Immunotherapy with Pembrolizumab will be prescribed if the tumor diameter exceeds 2 cm or if 
lymph nodes are positive. 
 
RT will consist of 26 Gy in 5 fractions or 40 Gy in 15 fractions if participants are under 50 years old 
with lymph node positivity. 
 

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6.10 Concomitant Therapy 
One capsule of 100 mg celecoxib or placebo will be taken after breakfast and one after supper, 
starting 7 days before RT and ending 14 days after RT. 
 
7 PARTICIPANT DISCONTINUATION OF TRIAL INTERVENTION 
AND DISCONTINUATION OR WITHDRAWAL FROM TRIAL 
7.1 Discontinuation of Trial Intervention for Individual Participants 
7.1.1 Permanent Discontinuation of Trial Intervention 
Participants who experience discomfort, such as rashes, headaches, or dizziness while taking 
celecoxib, should inform the research assistant or research nurse assigned to the clinical trial. They 
will then notify the promoter, who will discuss the situation with co-investigators Dr Michel Pavic, Dr 
Sawyna Provencher and Dr Isabelle Gauthier. The promoter will inform them of the meaning of the 
participant identification code to ensure appropriate clinical follow-up. Based on the severity of 
the adverse effect, they will decide whether or not to withdraw the participant from the trial. 
Participants withdrawn from the trial will continue their RT as planned. 
 
7.2 Participant Discontinuation or Withdrawal from the Trial 
Participants who no longer consent to participate in the trial will be withdrawn. See also section 7.1.1 
 
7.3 Management of Loss to Follow-Up 
Participant follow-up will last 5 years after treatment and will be carried out according to clinical 
guidelines, which consist of a clinical examination and a mammogram every year. No loss of follow-
up is expected for any participant. 
 
8 TRIAL ASSESSMENTS AND PROCEDURES 
8.1 Trial Assessments and Procedures Considerations 
This pilot study is to assess the feasibility of recruiting participants and implementing the study steps, 
with the intention of conducting a large-scale study in the future. Participants who experience 
discomfort, such as rashes, headaches, or dizziness while taking celecoxib, should inform the research 
assistant or research nurse assigned to the clinical trial. They will then notify the promoter, who will 
discuss the situation with co-investigators Dr Michel Pavic, Dr Sawyna Provencher and Dr Isabelle 
Gauthier. The promoter will inform them of the meaning of the participant identification code to 
ensure appropriate clinical follow-up. Based on the severity of the symptoms, they will decide 
whether or not to withdraw the participant from the trial. Participants withdrawn from the trial will 
continue their RT as planned. 
 
9 ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, PRODUCT 
COMPLAINTS, PREGNANCY AND POSTPARTUM INFORMATION, 
AND SPECIAL SAFETY SITUATIONS 
9.1 Definitions 
9.1.1 Definitions of Adverse Events 
Participants who experience discomfort - such as rashes, headaches, or dizziness - while taking 
celecoxib. 

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9.1.2 Definitions of Serious Adverse Events 
Serious adverse events include life-threatening event where the participant is at risk of death at the 
time of the event and required hospitalization. Serious adverse events may also include persistent or 
significant disability leading to a substantial disruption of the person’s ability to conduct normal life 
functions. 
Previous clinical trials reported a low increase of serious adverse events when celecoxib is taken for 
6 months and more at a dose above 200 mg daily (see monograph of MAR-CELECOXIB). These low 
but significant increases in severe adverse events were associated with: 
• Incidence of borderline-normal liver function test elevations (ALT, AST, alkaline 
phosphatase) of 6% for participants taking celecoxib capsules and 5% for placebo. 
• Increased risk of serious cardiovascular complications (such as myocardial infarction, stroke, 
or thrombotic events) was reported in participants presenting ischemic heart disease, 
cerebrovascular disease, heart failure (NYHA Class II-IV), or cardiovascular risk factors. 
• Cases of severe renal failure, some requiring dialysis and others resulting in death, have 
been reported in patients with renal impairment. 
• Stomach or intestinal problems such as ulcers, inflammation, bleeding, holes/perforation, 
blockage, or pain. 
 
In our trial, the risk of severe adverse events is expected to be very low because celecoxib will 
be administered at a daily dose of 200 mg for no longer than 40 days. In addition, participants will be 
excluded from the trial if they have experienced any of the following conditions in the last six months: 
• 
Stomach ulcer 
• 
Kidney disease: Glomerular filtration rate (GFR) lower than 50 mL/min 
• 
Liver disease: AST/ALT - 3 times the upper limit of normal; Bilirubine - 2 times the upper 
limit of normal; INR - 1.3 times the upper limit of normal; Cirrhose Child-Pugh B or more 
• 
Congestive heart failure: Left ventricular ejection fraction (LVEF) lower than 50% 
 
 
Will also be excluded participants demonstrating: 
• 
Hypersensitivity to celecoxib 
• 
History of allergic reactions to sulfonamides 
• 
History of asthma attacks, urticaria, or allergic reactions after taking acetylsalicylic acid 
(ASA) or another nonsteroidal anti-inflammatory drug 
• 
Presence of inflammatory bowel disease 
• 
Proven hyperkalemia 
 
9.2 Timing and Procedures for Collection and Reporting 
During the four visits of the participants corresponding to blood sampling, the research assistant will 
confirm with them that the taking of celecoxib or placebo is respected, and that the follow-up book 

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is correctly completed, and any experience discomforts are collected by the participants. Participants 
will be questioned by the research nurse to ensure that celecoxib is well tolerated. Participants who 
experience discomfort, such as rashes, headaches, or dizziness while taking celecoxib, should inform 
the research nurse or the research assistant. They will notify the promoter, Benoit Paquette, within 24 
hours, who will discuss the reported event with co-investigators Dr Michel Pavic, responsible for 
chemotherapy, and Drs Sawyna Provencher and Isabelle Gauthier, who will plan the RT. The clinicians 
will be notified about whether the participant received celecoxib or the placebo. They will evaluate 
the severity of the adverse effect and their possible relationship with the administration of celecoxib. 
The research staff will receive this report immediately. 
The promoter will compile the type, frequency, duration, and intensity of adverse effects on the 
CIOMS form and in the database file that collects all adverse effects. Unexpected serious adverse events 
associated with the drug but not fatal or life-threatening will be reported within 15 calendar days to 
the Canadian Minister of Health and the research staff. Unexpected serious adverse events associated 
with the drug and fatal or life-threatening events will be reported as soon as possible, but within 7 
calendar days by phone, followed by a written report within 8 calendar days. 
In the event of participant withdrawal from the trial, adverse events (serious or not) and their severity 
will be included in the scientific publications documenting the trial results. 
 
 
10 STATISTICAL CONSIDERATIONS 
10.1 General Considerations 
For this pilot trial, the analysis will include all eligible participant data at trial completion. 
 
10.2 Analysis Sets 
Participants will be divided into two arms: 1) celecoxib, and 2) placebo. For this pilot study, 15 
participants per arm will be enrolled. 
The primary objective of this pilot study is to assess the feasibility of recruiting participants and 
implementing the study steps, with the intention of conducting a large-scale study in the future. The 
secondary objective is to determine whether taking celecoxib will prevent the increase in cytokines 
induced by RT, some of which are known to stimulate the invasion capacity of cancer cells and 
the formation of metastases. This will be determined by collecting plasma samples at four time points: 
1) the day before the start of taking celecoxib or placebo, which corresponds to 7 days before starting 
RT, 2) the day of the start of RT and just before administering the 1st fraction of radiation, 3) after 
the 4th fraction of radiation, and 4) 14 days after the end of RT and stopping taking celecoxib or 
placebo. The impact of celecoxib on changes in 48 cytokines will be determined by Eve Technologies 
(Calgary) using laser bead multiplexing. 
The exploratory objective will determine whether preventing elevation induced by RT of cytokines 
by celecoxib will block the enhancement of cancer cell invasion and metastasis. This will be 
evaluated in preclinical models. The four plasma samples collected from each participant will be 
compared. Three TNBC cell lines will be incubated with these plasma samples. Using invasion 
chambers, the correlation between celecoxib-induced cytokine reduction and inhibition of RT-induced 
cancer cell invasion stimulation will be determined. These cells will also be injected intravenously 
into the tail of immunocompetent mice, and 28 days later, the reduction in the number of lung 
metastases with plasma collected from participants treated with celecoxib compared to those taking 
placebo will be determined. 

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10.3 Analyses of Demographics and Other Baseline Variables 
10.4 Analyses Associated with the Primary Objective 
10.4.1 Primary Objective 
The primary objective of this pilot study is to assess the feasibility of recruiting participants and 
implementing the study steps, with the intention of conducting a large-scale study in the 
future.10.4.1.1 Statistical Analysis Method 
When the large-scale study will be conducted, a Kaplan–Meier analysis will be used to perform 
univariate survival analysis and log-rank test to calculate the hazard ratio and compare two survival 
curves. For multivariate survival analysis, the multivariate Cox proportional hazards regression model 
was used to test the impact of celecoxib. All statistical analyses were performed with GraphPad 
Prism. A P value < 0.05 will be considered statistically significant. 
 
10.5 Analyses Associated with the Secondary Objective 
10.5.1 Secondary Objective 
 
The secondary objective is to determine whether taking celecoxib will prevent the increase in 
cytokines induced by RT, some of which are known to stimulate the invasion capacity of cancer 
cells and the formation of metastases. 
 
10.5.1.1 Statistical Analysis Method 
Identification of cytokines that differentiate patients who experience a relapse from those who do not 
will be done using Python programming leveraging machine-learning packages (e.g. Scikit-learn). 
These data will be scrutinized through various methods to establish correlations (positive or 
negative) using a correlation matrix and heatmap for both patient and cytokines. Principal Component 
Analysis (PCA) on standardized (mean removal and variance scaling) data will also be employed to 
reduce the dimensionality of the data, thereby allowing us to identify the most significant variables. 
Cytokine clusters will be determined using a Gaussian-Mixture-based unsupervised clustering 
algorithm (e.g. Variation Bayesian Gaussian Mixture). The thresholds for increases and decreases in 
the levels of these cytokines linked to relapse will then be determined. 
 
10.6 Analyses Associated with the Exploratory Objective 
The exploratory objective will determine whether preventing elevation induced by RT of cytokines 
by celecoxib will block the enhancement of cancer cell invasion and metastasis. 
 
The invasion assays will be performed 3 times in triplicate. For the metastasis formation assay, each 
group will include 8 mice. An Anova assay will be done using GraphPad Prism. A P value < 0.05 
will be considered statistically significant. 
 
10.7 Safety Analyses 
 
Celecoxib is currently indicated for the relief of symptoms associated with: osteoarthritis, rheumatoid, 
arthritis in adults and ankylosing spondylitis. It is also indicated in adults for the short-term relief (≤ 
7 days) of acute moderate to severe pain caused by: soft tissue and musculoskeletal trauma - 

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including sprains, orthopedic surgery, tooth extraction. 
 
The risk of serious side effects will be minimized since celecoxib will be administered for a short 
period (40 days or less) and at a dose not exceeding 200 mg/day. 
 
11 TRIAL OVERSIGHT AND OTHER GENERAL CONSIDERATIONS 
11.1 Regulatory and Ethical Considerations 
Pending approval from Health Canada, this clinical trial was approved by the ethics and scientific 
committees of the Clinical Research Center of the CIUSSS de l'Estrie CHUS. Protocol number: 
TNBC2025-5681 
 
This trial will be conducted in accordance with the protocol and with the following: 
• Ethical principles that have their origin in the Declaration of Helsinki for medical research 
involving human subjects 
• Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and the Council for International Organisations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
 
11.2 Trial Oversight 
Promoter : Benoit Paquette, Ph.D. 
Department of Medical Imaging and Radiation Sciences 
Faculty of Medicine and of Health Sciences Université de Sherbrooke 
3001, 12th Avenue North, Sherbrooke, Québec, Canada J1H 5N4 
 
11.3 Informed Consent Process 
Participants will be recruited and followed at our facility, CIUSSS de l'Estrie CHUS Sherbrooke, by 
Dr Sawyna Provencher (radiation oncologist), Dr Isabelle Gauthier (radiation oncologist) and Dr 
Michel Pavic (oncologist). 
 
The consent form will be presented to the participants by the treating radiation oncologist, the 
research nurse or the research assistant. 
 
11.4 Committees 
Not applicable. 
 
11.5 Insurance and Indemnity 
Not applicable. 
 
11.6 Risk-Based Quality Management 
Not applicable. 
 
11.7 Data Governance 

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Blood samples collected as part of this trial will be identified with a specific code. The patient names 
will not be identified on the samples, but a code will be used to link them. Decoding can only be 
performed by the promoter, Pr Benoit Paquette, or a person designated by him. 
 
The study data will be archived on the computer of the promoter and his research assistant. 
The blood samples will be stored for 10 years in a -20°C freezer in Pr Paquette laboratory, or until 
exhaustion. 
 
11.8 Data Protection 
The trial data will be archived on the computer of the promoter and his research assistant. 
All participant-related forms, such as the signed consent form, blood sampling certificates, and 
logbook filled by participants, will be kept in a locked file by the promoter. 
Trial records will be kept for 15 years after completion or discontinuation of the study. 
 
11.9 Source Data 
Participant source data, such as tumor size, lymph node status, chemotherapy type, RT plan, and 
administration or not of pembrolizumab, will be obtained by the research assistant from the CIUSSS 
de l'Estrie CHUS Sherbrooke computer registry using a secure internet line. 
 
11.10 Protocol Deviations 
Research assistant will give the participants the celecoxib or placebo bottle, explain the dosage to 
follow, and give them the follow-up logbook in which they will record the celecoxib or placebo intake, 
and any discomfort experienced, such as rashes, headaches, or dizziness. During the four participant 
visits corresponding to blood sampling, the research assistant will confirm with participants that the 
intake of celecoxib or placebo is respected. Participants who will not respect the protocol for celecoxib 
or placebo intake will be excluded from the trial. 
 
11.11 Early Site Closure 
The promoter already works on another trial with clinicians who recruit the participants and perform 
the 5-years follow-up. Early site closure is not expected. 
 
11.12 Data Dissemination 
As with other studies conducted by their team, Pr Paquette will publish the results of this trial in a 
peer-reviewed scientific journal, such as the International Journal of Radiation Biology & Related 
Studies in Physics, Chemistry & Medicine. These results will also be presented at the annual conference 
of Canadian Association of Radiation Oncology and at specialized conferences on breast cancer. 
 
12 APPENDIX: SUPPORTING DETAILS 
12.1 Clinical Laboratory Tests 
Clinical laboratory tests usually used in TNBC patients treated with chemotherapy, pembrolizumab, 
and RT will be performed. Eve Technology (Calgary) will identify and quantify cytokines in plasma 
collected from the participants. 

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12.2 Country/Region-Specific Differences 
 
Not applicable 
 
12.3 Prior Protocol Amendment 
Not applicable 
 
13 APPENDIX: GLOSSARY OF TERMS AND ABBREVIATIONS 
ASA, acetylsalicylic acid 
CIOMS, Council for International Organisations of Medical Sciences 
CIUSSS, Centre intégré universitaire de santé et de services sociaux 
COX-2, cyclooxygenase-2 
DFS, disease-free survival 
ER, estrogen receptor 
GCP, Good Clinical Practice 
GFR, Glomerular filtration rate 
HER-2, human epidermal growth factor receptor 2 
IL-6, interleukin-6 
LVEF, Congestive heart failure: Left ventricular ejection fraction 
NSAID, nonsteroidal anti-inflammatory drug 
PCA, Principal Component Analysis 
PR, progesterone receptor 
RT, radiotherapy 
 
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