NCT03515798
Version 0 to 1 · Institut Paoli-Calmettes
Patch inspector
Manual review pending.
arms_or_interventions_changeeligibility_criteria_change [
{
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"direction": "later",
"new_value": "2018-07-24",
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] 758a38cffb37423ffbfe0b4959a69763a873abdc5fecc8449e60433c4b72dba0/protocolSection/armsInterventionsModule/interventions/1/otherNames/0 arms_or_interventions_change Arms or interventions changes can alter treatment/comparator structure. 5-Fluorouracil, Epirubicine, Cyclophosphamide
(5-Fluorouracil), Epirubicine, Cyclophosphamide, Paclitaxel
/protocolSection/eligibilityModule/eligibilityCriteria eligibility_criteria_change Eligibility criteria changes can alter the studied population. <p>Inclusion Criteria:</p><ol><li>18 years or older,</li><li>Performance status 0 to 2,</li><li>Able to comply with the protocol,</li><li>Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen,</li><li>Patient must have signed a written informed consent form prior to any study specific screening procedures,</li><li><p>Previously untreated, histologically confirmed breast cancer and confirmed inflammatory breast cancer defined as follows:</p><p>- T4d any N following American Joint Committee on Cancer (AJCC)-7th version classification: diffuse Erythema and edema ("peau d'orange") of the breast, occupying at least 1/3 of the breast, with or without underlying palpable mass</p></li><li>HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluorescent/chromogenic in situ hybridization (FISH- or CISH-)</li><li>Hormone receptors status known,</li><li>No metastases,</li><li>Adequate hematologic function: absolute neutrophil count ≥ 1.2 x 109/L AND platelets ≥ 100 x 109 AND Hb ≥ 9 g/dL,</li><li>Adequate liver function: total bilirubin ≤ 1.5 ULN unless elevation is due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin AND - ASAT < 2.5 ULN AND ALAT < 2.5 ULN,</li><li>Adequate kidney function: serum creatinine ≤ 1.25 ULN or creatinine clearance ≥ 50 mL/min according to the Cockcroft and Gault formula AND no proteinuria (> 1 g/24 hours),</li><li>Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ultrasound methods),</li><li>International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 ULN AND normal TCA unless subject is receiving anticoagulant therapy, as long as PT or TCA is within therapeutic range of intended use of the anticoagulants,</li><li>Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of child bearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year. Note: Abstinence is acceptable if this is the established and preferred contraception for the subject,</li><li>Female subject of childbearing potential should have a negative urine or serum preg-nancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required,</li><li>Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.</li></ol><p>Exclusion Criteria:</p><ol><li>Has metastatic breast cancer,</li><li>Has HER2-positive breast cancer,</li><li>Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment,</li><li>Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,</li><li>Has a known history of active TB (Bacillus Tuberculosis),</li><li>Hypersensitivity to pembrolizumab or any of its excipients,</li><li>If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,</li><li>Has a known additional malignancy that progressed or required treatment in the last 5 years, Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer,</li><li>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 (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment,</li><li>Has history of/active pneumonitis requiring treatment with steroids or has history of/active interstitial lung disease,</li><li>Has an active infection requiring systemic therapy.</li><li>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,</li><li>Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial,</li><li>Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment,</li><li>Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent,</li><li>Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),</li><li>Has known active Hepatitis B (e.g., HBs Ag reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected),</li><li>Has received a live vaccine within 30 days of planned start of study therapy.</li></ol>
<p>Inclusion Criteria:</p><ol><li>Male/female participants who are at least 18 years of age on the day of signing informed consent</li><li>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.</li><li>Able to comply with the protocol,</li><li>Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen, or any other regimen of social security</li><li>Patient (or legally acceptable representative if applicable) has provided written informed consent for the trial,</li><li><p>Previously untreated, histologically confirmed diagnosis of breast cancer and confirmed inflammatory breast cancer defined as follows:</p><p>- T4d any N following American Joint Committee on Cancer (AJCC)-8th ver-sion 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.</p></li><li>HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluores-cent/chromogenic in situ hybridization (FISH- or CISH-)</li><li>Hormone receptors status known,</li><li>No metastases,</li><li>Have adequate organ function. Specimens must be collected within 10 days prior to the start of study treatment.</li><li>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.</li><li>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,</li><li>Adequate kidney function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 30 mL/min for participant with creatinine levels >1.5 × institutional ULN, Creatinine clear-ance (CrCl) should be calculated per institutional standard.</li><li>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,</li><li>Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ul-trasound methods),</li><li><p>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:</p><ol><li>Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR</li><li>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.</li></ol><p>Note: Abstinence is acceptable if this is the established and preferred contraception for the subject</p></li><li>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).</li></ol><p>Exclusion Criteria:</p><ol><li>Has metastatic breast cancer,</li><li>Has HER2-positive breast cancer,</li><li>Has bilateral breast cancer</li><li>If subject should receive 5-Fluorouracile (HR-positive patients), then no dihydropyrimi-dine deshydrogenase enzyme deficit as identified by plasma uracil dosage</li><li>Prior allogeneic stem cell or solid organ transplantation</li><li>A WOCBP who has a positive serum pregnancy test within 72 hours prior to randomiza-tion</li><li>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.</li><li>Has known active CNS disease or carcinomatous meningitis.</li><li>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 immunosuppres-sive therapy within 7 days prior to the first dose of study drug,</li><li>Has a known history of active TB (Bacillus Tuberculosis),</li><li>Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients,</li><li>If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,</li><li>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, squa-mous 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.</li><li>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,</li><li>Has a history of (non-infectious) pneumonitis that required steroids or has current pneu-monitis,</li><li>Has an active infection requiring systemic therapy.</li><li>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,</li><li>Has known psychiatric or substance abuse disorders that would interfere with coopera-tion with the requirements of the trial,</li><li>Is pregnant or breastfeeding, or expecting to conceive or father children within the pro-jected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment,</li><li>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).,</li><li>Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),</li><li>Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected)</li><li>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 vac-cines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.</li></ol>
/protocolSection/statusModule/startDateStruct/date start_timeline_change Start date changes are operational timeline signals. 2018-06-30
2018-07-24
/protocolSection/statusModule/startDateStruct/type start_timeline_change Start date changes are operational timeline signals. ESTIMATED
ACTUAL
/protocolSection/contactsLocationsModule/locations/0/facility Institut Sainte Catherine
Sint-Augustinus Hospital
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Antwerp
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Belgium
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Brussels
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Belgium
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Belgium
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UZ Gand
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Ghent
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UCL
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Leuven
/protocolSection/contactsLocationsModule/locations/4/country France
Belgium
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François Duhoux
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Mons
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Belgium
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Namur
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Belgium
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Amiens
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GOZY
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Angers
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Institut Sainte Catherine
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Avignon
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"contacts": [
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} /protocolSection/statusModule/statusVerifiedDate 2018-05
2019-05
/protocolSection/statusModule/lastUpdateSubmitDate 2018-05-03
2019-05-06
/protocolSection/statusModule/lastUpdatePostDateStruct/date 2018-05-04
2019-05-08
/protocolSection/sponsorCollaboratorsModule/collaborators/1 {
"name": "Oncodistinct",
"class": "UNKNOWN"
} /protocolSection/referencesModule/references/0 {
"pmid": "28564564",
"type": "BACKGROUND",
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"citation": "Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015 Mar 10;6(7):5449-64. doi: 10.18632/oncotarget.3216."
} /protocolSection/referencesModule/references/54 {
"pmid": "25527356",
"type": "BACKGROUND",
"citation": "Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, Bossuyt V, Pusztai L, Lannin DR, Rimm DL. PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunol Res. 2015 Apr;3(4):326-32. doi: 10.1158/2326-6066.CIR-14-0133. Epub 2014 Dec 19."
} /protocolSection/referencesModule/references/55 {
"pmid": "25940795",
"type": "BACKGROUND",
"citation": "Bertucci F, Finetti P, Colpaert C, Mamessier E, Parizel M, Dirix L, Viens P, Birnbaum D, van Laere S. PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget. 2015 May 30;6(15):13506-19. doi: 10.18632/oncotarget.3642."
} /protocolSection/referencesModule/references/56 {
"pmid": "15705911",
"type": "BACKGROUND",
"citation": "Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005 Feb 1;65(3):1089-96."
} /protocolSection/referencesModule/references/57 {
"pmid": "14871849",
"type": "BACKGROUND",
"citation": "Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004 Feb 1;64(3):1140-5. doi: 10.1158/0008-5472.can-03-3259."
} /protocolSection/referencesModule/references/58 {
"pmid": "21074057",
"type": "BACKGROUND",
"citation": "Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010 Oct;37(5):430-9. doi: 10.1053/j.seminoncol.2010.09.005."
} /protocolSection/referencesModule/references/59 {
"pmid": "14559843",
"type": "BACKGROUND",
"citation": "Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, Kasperbauer JL, Ballman KV, Chen L. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003 Oct 1;63(19):6501-5."
} /protocolSection/referencesModule/references/60 {
"pmid": "24829760",
"type": "BACKGROUND",
"citation": "Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014 Feb 18;2:3. doi: 10.1186/2051-1426-2-3. eCollection 2014."
} /protocolSection/referencesModule/references/61 {
"pmid": "15800326",
"type": "BACKGROUND",
"citation": "Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005 Apr 1;23(10):2346-57. doi: 10.1200/JCO.2005.00.240."
} /protocolSection/referencesModule/references/62 {
"pmid": "15771580",
"type": "BACKGROUND",
"citation": "Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-48. doi: 10.1146/annurev.immunol.23.021704.115611."
} /protocolSection/referencesModule/references/63 {
"pmid": "11698646",
"type": "BACKGROUND",
"citation": "Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13866-71. doi: 10.1073/pnas.231486598. Epub 2001 Nov 6."
} /protocolSection/referencesModule/references/64 {
"pmid": "15030777",
"type": "BACKGROUND",
"citation": "Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004 Mar;20(3):337-47. doi: 10.1016/s1074-7613(04)00051-2."
} /protocolSection/referencesModule/references/65 {
"pmid": "15240681",
"type": "BACKGROUND",
"citation": "Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004 Jul 15;173(2):945-54. doi: 10.4049/jimmunol.173.2.945."
} /protocolSection/referencesModule/references/66 {
"pmid": "15358536",
"type": "BACKGROUND",
"citation": "Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004 Sep 10;574(1-3):37-41. doi: 10.1016/j.febslet.2004.07.083."
} /protocolSection/referencesModule/references/67 {
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"type": "BACKGROUND",
"citation": "Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009 May;229(1):114-25. doi: 10.1111/j.1600-065X.2009.00767.x."
} /protocolSection/referencesModule/references/68 {
"pmid": "16227604",
"type": "BACKGROUND",
"citation": "Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005 Nov;25(21):9543-53. doi: 10.1128/MCB.25.21.9543-9553.2005."
} /protocolSection/referencesModule/references/69 {
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"citation": "Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010 Jul;236:219-42. doi: 10.1111/j.1600-065X.2010.00923.x."
} /protocolSection/referencesModule/references/70 {
"pmid": "28271869",
"type": "BACKGROUND",
"citation": "Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2."
} /protocolSection/statusModule/overallStatus NOT_YET_RECRUITING
RECRUITING
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"value": "<p>Inclusion Criteria:</p><ol><li>Male/female participants who are at least 18 years of age on the day of signing informed consent</li><li>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.\nNote: may consider ECOG PS 2 if good rationale provided and discussed with Sponsor team.</li><li>Able to comply with the protocol,</li><li>Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen, or any other regimen of social security</li><li>Patient (or legally acceptable representative if applicable) has provided written informed consent for the trial,</li><li><p>Previously untreated, histologically confirmed diagnosis of breast cancer and confirmed inflammatory breast cancer defined as follows:</p><p>- T4d any N following American Joint Committee on Cancer (AJCC)-8th ver-sion 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.</p></li><li>HER2 negative tumors by immunohistochemistry (IHC 0 or 1+) or fluores-cent/chromogenic in situ hybridization (FISH- or CISH-)</li><li>Hormone receptors status known,</li><li>No metastases,</li><li>Have adequate organ function.\nSpecimens must be collected within 10 days prior to the start of study treatment.</li><li>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.</li><li>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,</li><li>Adequate kidney function: serum creatinine ≤ 1.5 ULN or creatinine clearance ≥ 30 mL/min for participant with creatinine levels >1.5 × institutional ULN, Creatinine clear-ance (CrCl) should be calculated per institutional standard.</li><li>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,</li><li>Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% (isotopic or ul-trasound methods),</li><li><p>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:</p><ol><li>Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR</li><li>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.</li></ol><p>Note: Abstinence is acceptable if this is the established and preferred contraception for the subject</p></li><li>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).</li></ol><p>Exclusion Criteria:</p><ol><li>Has metastatic breast cancer,</li><li>Has HER2-positive breast cancer,</li><li>Has bilateral breast cancer</li><li>If subject should receive 5-Fluorouracile (HR-positive patients), then no dihydropyrimi-dine deshydrogenase enzyme deficit as identified by plasma uracil dosage</li><li>Prior allogeneic stem cell or solid organ transplantation</li><li>A WOCBP who has a positive serum pregnancy test within 72 hours prior to randomiza-tion</li><li>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.</li><li>Has known active CNS disease or carcinomatous meningitis.</li><li>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 immunosuppres-sive therapy within 7 days prior to the first dose of study drug,</li><li>Has a known history of active TB (Bacillus Tuberculosis),</li><li>Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients,</li><li>If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy,</li><li>Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.\nNote: Participants with basal cell carcinoma of the skin, squa-mous cell carcinoma of the skin, or carcinoma in situ (e.g.\nbreast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.</li><li>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).\nReplacement therapy (e.g.\nthyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment,</li><li>Has a history of (non-infectious) pneumonitis that required steroids or has current pneu-monitis,</li><li>Has an active infection requiring systemic therapy.</li><li>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,</li><li>Has known psychiatric or substance abuse disorders that would interfere with coopera-tion with the requirements of the trial,</li><li>Is pregnant or breastfeeding, or expecting to conceive or father children within the pro-jected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment,</li><li>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).,</li><li>Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),</li><li>Has known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C virus infection (e.g., HCV RNA [qualitative] is detected)</li><li>Has received a live vaccine within 30 days prior to the first dose of study drug.\nExamples 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.\nSeasonal influenza vaccines for injection are generally killed virus vac-cines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.</li></ol>"
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