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JOURNAL ONKOLOGIE – STUDIE

Study of Pembrolizumab (MK-3475) Versus Placebo in Combination With Neoadjuvant Chemotherapy & Adjuvant Endocrine Therapy in the Treatment of Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (MK-3475-756/KEYNOTE-756)

Rekrutierend

NCT-Nummer:
NCT03725059

Studienbeginn:
Dezember 2018

Letztes Update:
07.06.2021

Wirkstoff:
Pembrolizumab (K), Placebo (P), Paclitaxel (X), Epirubicin (E), Cyclophosphamide (C), Endocrine therapy, Doxorubicin (A)

Indikation (Clinical Trials):
Breast Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Merck Sharp & Dohme Corp.

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme Corp.

Kontakt

Studienlocations
(3 von 242)

HELIOS Dr. Horst Schmidt Kliniken Wiesbaden ( Site 1004)
65199 Wiesbaden
(Hessen)
GermanyAbgeschlossen» Google-Maps
Cancer Treatment Centers of America at Western Regional Medical Center ( Site 0001)
85338 Goodyear
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 623-207-3000
» Ansprechpartner anzeigen
MercyOne Waterloo Cancer Center ( Site 0016)
50702 Waterloo
United StatesAbgeschlossen» Google-Maps
CTCA Southwestern ( Site 0074)
74133 Tulsa
United StatesAbgeschlossen» Google-Maps
Cancer Treatment Centers of America-Eastern Regional Medical Center ( Site 0076)
19124 Philadelphia
United StatesAbgeschlossen» Google-Maps
Imelda Ziekenhuis Bonheiden ( Site 0703)
1932 Bonheiden
BelgiumAbgeschlossen» Google-Maps
Associacao Hospitalar Moinhos de Vento ( Site 0201)
90035-001 Porto Alegre
BrazilAktiv, nicht rekrutierend» Google-Maps
Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 0202)
90610-000 Porto Alegre
BrazilRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +555133203039
» Ansprechpartner anzeigen
Instituto Nacional de Cancer - INCA HC III ( Site 0200)
20560-120 Rio de Janeiro
BrazilAktiv, nicht rekrutierend» Google-Maps
CHR-METZ-THIONVILLE - Hopital de Mercy ( Site 0919)
57085 Metz
FranceAbgeschlossen» Google-Maps
Kaplan Medical Center ( Site 1703)
7661041 Rehovot
IsraelAbgeschlossen» Google-Maps
National Hospital Organization - Osaka National Hospital - Institute For Clinical Research ( Site 26
540-0006 Osaka
JapanRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +81669421331
» Ansprechpartner anzeigen
Tauranga Hospital ( Site 2302)
3112 Tauranga
New ZealandAbgeschlossen» Google-Maps
Canterbury Regional Cancer & Blood Services ( Site 2303)
8011 Christchurch
New ZealandAbgeschlossen» Google-Maps
Capital & Coast District Health Board - Wellington Hospital ( Site 2301)
6021 Wellington
New ZealandAbgeschlossen» Google-Maps
Wojewodzki Szpital Specjalistyczny nr 4 w Bytomiu ( Site 1807)
41-900 Bytom
PolandAbgeschlossen» Google-Maps
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (
02-781 Warszawa
PolandRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +48502626262
» Ansprechpartner anzeigen
Republican Clinical Oncology Dispensary of Republic of Bashkortostan ( Site 1909)
450054 Ufa
Russian FederationAbgeschlossen» Google-Maps
Central Clinical Hospital with outpatient Clinic ( Site 1907)
121359 Moscow
Russian FederationAktiv, nicht rekrutierend» Google-Maps
Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 1900)
197758 Saint Petersburg
Russian FederationRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +78124399560
» Ansprechpartner anzeigen
Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 1363)
08908 Hospitalet de Llobregat
SpainRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +34932607744
» Ansprechpartner anzeigen
MI KhRC Kherson Regional Oncology Dispensary ( Site 2713)
73000 Antonivka Village
UkraineAbgeschlossen» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

Study participants will receive 8 cycles of neoadjuvant study treatment and then will undergo

surgery for their breast cancer. After surgery, participants will receive 9 cycles of study

treatment and up to 10 years of variable endocrine therapy. Each cycle is 21 days long.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Has a localized invasive breast ductal adenocarcinoma, confirmed by the local

pathologist, that includes either T1c-T2 (tumor size ≥2 cm), clinical node stage

(cN)1-cN2, or T3-T4, cN0-cN2. Note: Inflammatory breast cancer is allowed.

- Has centrally confirmed ER+/HER2-, Grade 3 breast cancer of ductal histology,

according to the most recent American Society of Clinical Oncology/College of American

Pathologist guidelines.

- Provides a new or recently obtained core needle biopsy, consisting of multiple cores,

taken from the primary breast tumor(s) for central determination of HR status (ER and

progesterone receptor), HER2, grade, and PD-L1 status.

Note: Sponsor agreement is required for formalin-fixed paraffin-embedded (FFPE) tumor

tissue sample or slides that were obtained greater than 60 days prior to the date that the

documented informed consent was obtained.

- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as

assessed within 10 days prior to initiation of study treatment.

- Male participants must agree to use contraception during the treatment period and for

at least 12 months (for participants who received cyclophosphamide) or 6 months (for

participants who did not receive cyclophosphamide) after the last dose of study

treatment and refrain from donating sperm during this period.

- Female participants must agree to use effective contraception during the treatment

period and for at least 12 months (for participants who received cyclophosphamide) or

6 months (for participants who did not receive cyclophosphamide) after the last dose

of study treatment with pembrolizumab or placebo.

- Has adequate organ function.

Exclusion Criteria:

- Has a history of non-infectious pneumonitis that required treatment with steroids or

has current pneumonitis.

- Has breast cancer with lobular histology.

- Has bilateral invasive breast cancer.

- Has metastatic (Stage IV) breast cancer.

- Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants

of the breast).

- Has any of the following clinical lymph node staging per current American Joint

Committee on Cancer (AJCC) staging criteria for breast cancer staging based on

radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.

- Has ER-, progesterone receptor positive breast cancer.

- Has undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or

has undergone sentinel lymph node biopsy prior to study treatment.

- Has a known additional, invasive, malignancy that is progressing or required active

treatment in the last 5 years.

Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the

skin, ductal breast carcinoma in situ, or cervical carcinoma in situ that has undergone

potentially curative therapy are not excluded.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

(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 treatment.

- Has an 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) Note: Replacement therapy (e.g. thyroxine, insulin, or

physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)

is not considered a form of systemic treatment.

- Has a known history of active tuberculosis (Bacillus tuberculosis).

- Has an active infection requiring systemic therapy.

- Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit

of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

performed at screening.

- Has other significant cardiac disease, such as: 1) History of myocardial infarction,

acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6

months. or 2) Congestive heart failure (CHF) New York Heart Association (NYHA) Class

II-IV or history of CHF NYHA Class III or IV.

- Has a known history of human immunodeficiency virus (HIV) infection.

- Has a known history of hepatitis B or known active hepatitis C virus infection.

- Has received prior treatment for breast cancer.

- Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),

anti-programmed cell death-ligand 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. cytotoxic

T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).

- Has received a live vaccine within 30 days prior to the first dose of study treatment.

- Has severe hypersensitivity (≥Grade 3) to any of the components or excipients used in

the study treatments.

- Is/was enrolled in a study of an investigational agent and received study therapy, or

used an investigational device within 4 weeks (12 months for an investigational agent

or device with anticancer or antiproliferative properties) prior to the first dose of

study treatment.

- Is pregnant, breastfeeding, or expecting to conceive or father children within the

projected duration of the study, starting with the screening visit through 12 months

(for participants who received cyclophosphamide) or 6 months (for participants who did

not receive cyclophosphamide) after the last dose of study treatment.

Studien-Rationale

Primary outcome:

1. Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0 (Time Frame - Up to approximately 7 months (Time of surgery)):
The pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by American Joint Committee on Cancer (AJCC) staging criteria (7th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pathological Complete Response (pCR) using the definition of (ypT0/Tis ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

2. Event-Free Survival (EFS) (Time Frame - Up to approximately 12 years):
EFS is defined as the time from randomization to disease progression that: precludes surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator will be presented.

Secondary outcome:

1. Overall Survival (OS) (Time Frame - Up to approximately 12 years):
OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies will be presented.

2. pCR Rate Using the Definition of ypT0ypN0 (Time Frame - Up to approximately 7 months (Time of surgery)):
pCR rate (ypT0ypN0) is defined as the percentage of participants without residual invasive or in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the definition of (ypT0ypN0) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

3. pCR Rate Using the Definition of ypT0/Tis (Time Frame - Up to approximately 7 months (Time of surgery)):
pCR rate (ypT0/Tis) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen (independent of lymph node involvement) after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the definition of ypT0/Tis will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

4. pCR Rate Using the Definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in Participants With a Combined Positive Score [CPS] ≥1 (Time Frame - Up to approximately 7 months (Time of surgery)):
pCR rates were calculated using the definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 after completion of neoadjuvant systemic therapy by AJCC staging criteria (7th edition) assessed by the local pathologist at the time of surgery. The percentage of participants with a pCR using the three definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in participants with a CPS ≥1 (with a positive Programmed Cell Death-Ligand 1 [PD-L1] tumor status) will be presented for pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.

5. EFS in Participants With a CPS ≥1 (Time Frame - Up to approximately 12 years):
EFS is defined as the time from randomization to disease progression that: precludes surgery, results in a local or distant recurrence, results in a second primary malignancy, or death due to any cause whichever occurs first. The EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator for participants with a CPS ≥1 will be presented.

6. OS in Participants With a CPS ≥1 (Time Frame - Up to approximately 12 years):
OS is defined as the time from date of randomization to date of death due to any cause. The OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies for participants with a CPS ≥1 will be presented.

7. Number of Participants Experiencing an Adverse Event (AE) (Time Frame - Up to approximately 15 months):
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented.

8. Number of Participants Experiencing a Serious Adverse Event (SAE) (Time Frame - Up to approximately 17 months):
An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, Is life-threatening, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity or Is a congenital anomaly/birth defect. The number of participants who experience an SAE while receiving pembrolizumab or placebo (including 3 months of safety follow up) will be presented.

9. Number of Participants Experiencing an Immune-related AE (irAE) (Time Frame - Up to approximately 15 months):
Some AEs that may occur in this study that are known to be related to pembrolizumab immunotherapy treatment and may include: pneumonitis, diarrhea/colitis, aspartate aminotransferase/alanine aminotransferase (AST/ALT) elevation or increased bilirubin, Type 1 diabetes mellitus or hyperglycemia, hypophysitis, hyperthyroidism, hypothyroidism, nephritis and renal dysfunction, and myocarditis. The number of participants who experience an irAE while receiving pembrolizumab or placebo (including 1 month of safety follow up) will be presented.

10. Number of Study Treatment Discontinuations Due to AEs (Time Frame - Up to approximately 14 months):
The number of participants who discontinue study treatment (pembrolizumab or placebo) due to an AE will be presented.

11. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core 30 (QLQ-C30) Score (Time Frame - Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days.):
The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses for each of 28 items are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome, and responses for each of 2 items (overall health and overall quality of life) are given on a 7-point scale (1=Very poor to 7=Excellent), with a higher score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC-QLQ-C30 scores for participants will be presented.

12. Change from Baseline in EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) Score (Time Frame - Baseline (Cycle 1 Day 1 in Treatment 1) and Cycles 1 and 4 Day 1 in Treatment 2 (Up to approximately 5 months) Each cycle is 21 days.):
The EORTC QLQ-BR23 is a 23-item questionnaire developed to assess the quality of life in women with breast cancer. Responses for each item are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The change from Baseline to end of treatment (up to Cycle 4 Day 1) in EORTC QLQ-BR23 score for participants will be presented.

Studien-Arme

  • Experimental: Pembrolizumab+Chemotherapy (KX/KA[E]C)
    In the neoadjuvant setting, participants receive pembrolizumab (K) 200 mg via intravenous (IV) infusion once every 3 weeks (Q3W) + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by pembrolizumab 200 mg via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion Q3W for 4 cycles (Treatment 2). At 3 to 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive pembrolizumab 200 mg via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.
  • Placebo Comparator: Placebo+Chemotherapy (PX/PA[E]C)
    In the neoadjuvant setting, participants receive placebo (P; normal saline or dextrose) via IV infusion Q3W + paclitaxel (X) 80 mg/m^2 via IV infusion once weekly (QW) for 4 cycles (Treatment 1), followed by placebo via IV infusion + doxorubicin or epirubicin (A or E; 60 mg/m^2 or 100 mg/m^2) via IV infusion Q3W + cyclophosphamide (C) 600 mg/m^2 via IV infusion Q3W for 4 cycles (Treatment 2). At 3 to 6 weeks after last cycle of neoadjuvant treatment, participants will undergo surgery for their breast cancer. After surgery, participants will begin adjuvant study treatment. In the adjuvant setting, participants receive placebo via IV infusion Q3W for 9 cycles + variable endocrine therapy for up to 10 years. Each cycle is 21 days long.

Geprüfte Regime

  • Pembrolizumab (K) (MK-3475 / KEYTRUDA® / ):
    IV infusion Q3W
  • Placebo (P):
    Normal saline or dextrose IV infusion Q3W
  • Paclitaxel (X) (TAXOL®):
    IV infusion QW
  • Doxorubicin (A) (ADRIAMYCIN®):
    IV infusion Q3W
  • Epirubicin (E) (ELLENCE®):
    IV infusion Q3W
  • Cyclophosphamide (C) (CYTOXAN®):
    IV infusion Q3W
  • Endocrine therapy:
    Variable endocrine therapy for up 10 years
  • Radiation therapy:
    Variable radiation therapy per local standard of care
  • Surgery:
    Surgery for breast cancer

Quelle: ClinicalTrials.gov


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