This phase II multicentre randomized open-label study will assess the safety and efficacy of
Pembrolizumab in combination with standard chemotherapy in inflammatory breast cancer.
Pembrolizumab will be administered every 3 weeks during the neoadjuvant chemotherapy. Tissue
and blood samples will be collected pre- and post-treatment for translational research.
Inflammatory breast cancer (IBC) is a rare and highly aggressive subtype of locally advanced
breast cancer representing approximately 5% of all breast cancers that requires immediate
aggressive treatment. Significant progress has been made in recent years using a combination
of treatments, including neoadjuvant chemotherapy, surgery and radiation therapy.
Accumulating data indicate a prognostic and/or predictive impact for immune-response
variables in BC. Recent data, suggest that PD-L1 is overexpressed in a significant number of
BC, notably in IBC and may have significant prognostic or predictive value. Furthermore it
may be targeted to restore or boost functional antitumor immunity. Pembrolizumab, a
PD-1-directed monoclonal antibody is already registered and has an out-standing activity in
advanced melanoma and NSCLC patients, with promising results in several other tumor types,
including triple-negative BC, and a favorable profile of tolerance.
Thus, potential benefits of pembrolizumab in combination with a conventional cytotoxic
backbone may be considered as high in HER2-negative IBC.
The aim of the study is to assess the pathological complete response rate following
neoadjuvant EC-paclitaxel chemotherapy plus pembrolizumab and to assess if neoadjuvant
chemotherapy with anthracycline-based induction in combination with pembrolizumab exposes IBC
patients to significant toxicity. rates.
1. Male/female participants who are at least 18 years of age on the day of signing
2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Evaluation of ECOG is to be performed within 7 days prior to the date of
randomization. Note: may consider ECOG PS 2 if good rationale provided and discussed
with Sponsor team.
3. Able to comply with the protocol,
4. Patient affiliated to the national "Social Security" regimen or beneficiary of this
regimen, or any other regimen of social security
5. Patient (or legally acceptable representative if applicable) has provided written
informed consent for the trial,
6. Previously untreated, histologically confirmed diagnosis of breast cancer and
confirmed inflammatory breast cancer defined as follows:
- T4d any N following American Joint Committee on Cancer (AJCC)-8th version
classification: breast erythema, edema and/or peau d'orange, occupying at least 1/3 of
the breast, with or without underlying palpable mass, duration of history of no more
than 6 months.
7. HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluorescent/chromogenic
in situ hybridization (FISH- or CISH-)
8. Hormone receptors status known,
9. No metastases,
10. Have adequate organ function. Specimens must be collected within 10 days prior to the
start of study treatment.
11. Adequate hematologic function: absolute neutrophil count ≥ 1.5 x 109/L AND platelets ≥
100 x 109 AND Hb ≥ 9.0 g/dL or ≥5.6 mmol/L, Criteria must be met without
erythropoietin dependency and without packed red blood cell (pRBC) transfusion within
last 2 weeks.
12. Adequate liver function: total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for
participants with total bilirubin levels >1.5 × ULN AND - ASAT ≤ 2.5 ULN AND ALAT ≤
13. Adequate kidney function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 30
mL/min for participant with creatinine levels >1.5 × institutional ULN, Creatinine
clearance (CrCl) should be calculated per institutional standard.
14. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 ULN unless subject
is receiving anticoagulant therapy, as long as PT or TCA is within therapeutic range
of intended use of the anticoagulants,
15. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic
or ultrasound methods),
16. A female participant is eligible to participate if she is not pregnant (see Appendix
3), not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
treatment period and for at least 12 months after the last dose of
cyclophosphamide and 4 months after the last dose of pembrolizumab, whichever
Note: Abstinence is acceptable if this is the established and preferred contraception
for the subject
17. A male participant must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 6 months after the last dose of
study treatment and refrain from donating sperm during this period (corresponding to
time needed to eliminate any study treatments plus an additional 120 days (a
spermatogenesis cycle) for study treatments with risk of genotoxicity at any dose).
1. Has metastatic breast cancer,
2. Has HER2-positive breast cancer,
3. Has bilateral breast cancer
4. Prior allogeneic stem cell or solid organ transplantation
5. A WOCBP who has a positive serum pregnancy test within 72 hours prior to
6. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment, Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.
7. Has known active CNS disease or carcinomatous meningitis.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug,
9. Has a known history of active TB (Bacillus Tuberculosis),
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients,
11. If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy,
12. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
13. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment,
14. Has a history of (non-infectious) pneumonitis that required steroids or has current
15. Has an active infection requiring systemic therapy.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator,
17. Has known psychiatric or substance abuse disorders that would interfere with
coopera-tion with the requirements of the trial,
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment,
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX 40, CD137).,
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
21. Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C
virus infection (e.g., HCV RNA [qualitative] is detected)
22. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.