Study of Immunotherapy in Combination With Chemotherapy in HER2-negative Inflammatory Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Prospective Multicenter Open-label, Randomized Phase II Study of Pembrolizumab in Combination With Neoadjuvant EC-Paclitaxel Regimen in HER2-negative Inflammatory Breast Cancer.

Conditions
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Inflammatory Breast Cancer

Intervention / Treatment
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* Drug: Pembrolizumab Injection
* Drug: neoadjuvant EC-paclitaxel chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male/female participants who are at least 18 years of age on the day of signing informed consent 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. Able to comply with the protocol, Patient affiliated to the national Social Security regimen or beneficiary of this regimen, or any other regimen of social security Patient (or legally acceptable representative if applicable) has provided written informed consent for the trial, 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. HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluorescent/chromogenic in situ hybridization (FISH- or CISH-) Hormone receptors status known, No metastases, Have adequate organ function. Specimens must be collected within 10 days prior to the start of study treatment. 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. 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 ≤ 2.5 ULN, 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. 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, Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ultrasound methods), 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: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR 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 come last. Note: Abstinence is acceptable if this is the established and preferred contraception for the subject 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). Exclusion Criteria: Has metastatic breast cancer, Has HER2-positive breast cancer, Has bilateral breast cancer Prior allogeneic stem cell or solid organ transplantation A WOCBP who has a positive serum pregnancy test within 72 hours prior to randomiza-tion 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. Has known active CNS disease or carcinomatous meningitis. 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, Has a known history of active TB (Bacillus Tuberculosis), Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy, 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 excluded. 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, Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis, Has an active infection requiring systemic therapy. 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, Has known psychiatric or substance abuse disorders that would interfere with coopera-tion with the requirements of the trial, 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, 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)., Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>EC Paclitaxel + Pembrolizumab Injection | Drug: Pembrolizumab Injection<br>* Patients will receive intravenously 1 dose of Pembrolizumab every 3 weeks<br>* Other names: MK3475;Drug: neoadjuvant EC-paclitaxel chemotherapy<br>* The cytotoxic regimen is a combination of dose-dense EC, followed by weekly paclitaxel<br>* Other names: Epirubicine, Cyclophosphamide, Paclitaxel;|
| Active Comparator: Standard neoadjuvant chemotherapy<br>EC Paclitaxel alone | Drug: neoadjuvant EC-paclitaxel chemotherapy<br>* The cytotoxic regimen is a combination of dose-dense EC, followed by weekly paclitaxel<br>* Other names: Epirubicine, Cyclophosphamide, Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central evaluation of pathological complete response rate | absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system) | Following completion of neoadjuvant systemic treatment, an average of 24 weeks | 
| Dose Limiting Toxicity (DLT) rates | incidence of DLT during the 21 days following the first administration of pembrolizumab in combination with EC, will be assessed separately in the first 3 patients of each stratum (HR+ and HR-). DLTs will be defined according to CTCAE. | during 21 days following the first administration of pembrolizumab | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| occurrence of serious adverse events and adverse events starting grade 2 or grade 1 (run-in period) | according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | during 21 days following the first administration of pembrolizumab | 
| Local evaluation of pathological complete response rate | defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of NAST (i.e., ypT0/is, ypN0 in the current AJCC staging system) | Following completion of neoadjuvant systemic treatment, an average of 24 weeks | 
| Invasive disease-free survival (IDFS) | time from surgery to the first documented occurrence of an event, defined as: Ipsilateral invasive breast tumor recurrence, Ipsilateral local-regional invasive breast cancer recurrence, Distant recurrence, Contralateral invasive breast cancer, Death from any cause | 3 years | 
| Invasive disease-free survival (IDFS) | time from surgery to the first documented occurrence of an event, defined as: Ipsilateral invasive breast tumor recurrence, Ipsilateral local-regional invasive breast cancer recurrence, Distant recurrence, Contralateral invasive breast cancer, Death from any cause | 5 years | 
| Event free survival (EFS) | time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non invasive]), or death from any cause) | 3 years | 
| Event free survival (EFS) | time from randomization to disease progression, disease recurrence (local, regional, distant, or contralateral [invasive or non invasive]), or death from any cause) | 5 years | 
| Overall survival (OS) | time from randomization to death from any cause | 3 years | 
| Overall survival (OS) | time from randomization to death from any cause | 5 years |