NCT03725059|Active Not RecruitingPhase 3DMCFDA Drug

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)

A Randomized, Double-Blind, Phase III Study of Pembrolizumab Versus Placebo in Combination With Neoadjuvant Chemotherapy and Adjuvant Endocrine Therapy for the Treatment of High-Risk Early-Stage Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (ER+/HER2-) Breast Cancer (KEYNOTE-756)

Merck Sharp & Dohme LLC ClinicalTrials.gov

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8 other identifiers

3475-756MK-3475-756194604KEYNOTE-7562023-506921-12-00jRCT2080224535U1111-1294-63522017-004869-27

Study Type

interventional

Target

1,240

Locations

23 countries

Sites

243

Timeline

RegisteredOct 2018

StartedDec 2018

CompletionJan 2031

Brief Summary

The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) versus placebo in combination with neoadjuvant (pre-surgery) chemotherapy and adjuvant (post-surgery) endocrine therapy in the treatment of adults who have high-risk early-stage estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. The primary study hypotheses are: 1) pembrolizumab is superior to placebo, both in combination with the protocol-specified neoadjuvant anticancer therapy, as assessed by pathological Complete Response (pCR) rate defined by the local pathologist, and 2) pembrolizumab is superior to placebo (both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies) as assessed by Event-Free Survival (EFS) as determined by the investigator. The study is considered to have met its primary objective if pembrolizumab is superior to placebo with respect to either pCR (ypT0/Tis ypN0) or EFS.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Strong global presence with extensive site network

Enrollment

1,240

participants targeted

Target at P75+ for phase_3 breast-cancer

Timeline

57mo left

Started Dec 2018

Longer than P75 for phase_3 breast-cancer

Geographic Reach

23 countries

243 active sites

Status

active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

12.1 years study duration

Study Progress61%

Dec 2018Jan 2031

First Submitted

Initial submission to the registry

October 29, 2018

Completed

1 day until next milestone

First Posted

Study publicly available on registry

October 30, 2018

Completed

2 months until next milestone

Study Start

First participant enrolled

December 27, 2018

Completed

12.1 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 24, 2031

Expected

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 24, 2031

Last Updated

July 11, 2025

Status Verified

July 1, 2025

Enrollment Period

12.1 years

First QC Date

October 29, 2018

Last Update Submit

July 8, 2025

Conditions

Breast Cancer

Keywords

PD1PD-1PDL1PD-L1

Outcome Measures

Primary Outcomes (2)

Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0
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 (8th 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.
Up to approximately 7 months (Time of surgery)
Event-Free Survival (EFS)
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.
Up to approximately 12 years

Secondary Outcomes (12)

Overall Survival (OS)
Up to approximately 12 years
pCR Rate Using the Definition of ypT0ypN0
Up to approximately 7 months (Time of surgery)
pCR Rate Using the Definition of ypT0/Tis
Up to approximately 7 months (Time of surgery)
pCR Rate Using the Definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in Participants With a Combined Positive Score [CPS] ≥1
Up to approximately 7 months (Time of surgery)
EFS in Participants With a CPS ≥1
Up to approximately 12 years
+7 more secondary outcomes

Study Arms (2)

Pembrolizumab+Chemotherapy (KX/KA[E]C)

EXPERIMENTAL

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 either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m\^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 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.

Biological: Pembrolizumab (K)Drug: Paclitaxel (X)Drug: Doxorubicin (A)Drug: Epirubicin (E)Drug: Cyclophosphamide (C)Drug: Endocrine therapyRadiation: Radiation therapyProcedure: Surgery

Placebo+Chemotherapy (PX/PA[E]C)

PLACEBO COMPARATOR

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 either in Q2W or Q3W + cyclophosphamide (C) 600 mg/m\^2 via IV infusion either in Q2W or Q3W for 4 cycles (Treatment 2). At no more than 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.

Drug: Placebo (P)Drug: Paclitaxel (X)Drug: Doxorubicin (A)Drug: Epirubicin (E)Drug: Cyclophosphamide (C)Radiation: Radiation therapyProcedure: Surgery

Interventions

Pembrolizumab (K)BIOLOGICAL

IV infusion Q3W

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab+Chemotherapy (KX/KA[E]C)

Placebo (P)DRUG

Normal saline or dextrose IV infusion Q3W

Placebo+Chemotherapy (PX/PA[E]C)

Paclitaxel (X)DRUG

IV infusion QW

Also known as: TAXOL®