A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab plus Chemotherapy vs Placebo plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Mar 2017 → 15 Oct 2025

Decision date (initial)

2023-02-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2022-501382-49-00

EudraCT number

2016-004740-11

WHO UTN

U1111-1280-2361

ClinicalTrials.gov

NCT03036488

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

1.To evaluate the rate of pCR using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist at the time of definitive surgery in subjects with locally advanced TNBC.
2.To evaluate the event-free survival (EFS) as assessed by investigator in subjects with locally advanced TNBC.

Secondary objectives 8

1. To evaluate overall survival (OS) in subjects with locally advanced TNBC tumors.
2. To evaluate the rate of pCR using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) as assessed by the local pathologist at the time of definitive surgery in subjects with locally advanced TNBC and in individuals with programmed death ligand 1 (PD-L1) positive (+) tumors (combined positive score [CPS] ≥1).
3. To evaluate the rate of pCR using the definition of (ypT0/Tis ypN0) (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist at the time of definitive surgery in individuals with PD-L1 (+) tumors (CPS ≥1).
4. To evaluate the EFS as assessed by investigator in individuals with PD-L1 (+) tumors (CPS ≥1).
5. To evaluate the rate of pCR using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) as assessed by the local pathologist at the time of definitive surgery in subjects with locally advanced TNBC and in individuals with PD-L1 (+) tumors (CPS ≥1).
6. To evaluate overall survival (OS) in individuals with PD-L1 (+) tumors (CPS ≥1).
7. To determine the safety and tolerability of pembrolizumab in combination with neoadjuvant chemotherapy and pembrolizumab as adjuvant therapy in locally advanced TNBC subjects, within and across the neoadjuvant and adjuvant phases.
8. To evaluate health-related quality-of-life (QoL) assessments in TNBC subjects and in subjects with PD-L1 (+) tumors (CPS ≥1) using the European Organisation for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30) and EORTC Breast Cancer–Specific QoL Questionnaire (QLQ-BR23) within and across the neoadjuvant and adjuvant treatment phases.

Conditions and MedDRA coding

Triple Negative Breast Cancer (TNBC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Has newly diagnosed, locally advanced, centrally confirmed triple negative breast cancer (TNBC), as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
2. Has previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee of Cancer (AJCC) staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment: T1c, N1-N2; T2, N0-N2; T3, N0-N2; T4a-d, N0-N2
3. Provides a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory.
4. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.
5. Demonstrates adequate organ function.
6. Males and female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and 6 months after the last dose of study treatment for participants who did not.

Exclusion criteria 15

1. Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
2. Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
3. Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]) or has previously participated in a pembrolizumab (MK-3475) clinical study.
4. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 4 weeks of the first dose of treatment in this current study.
5. Has received a live vaccine within 30 days of the first dose of study treatment.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
8. Has a known history of Human Immunodeficiency Virus (HIV).
9. Has known active Hepatitis B or Hepatitis C.
10. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
13. Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for participants who have not.
14. Has a known hypersensitivity to the components of the study treatment or its analogs.
15. Has a known history of active tuberculosis (TB, Bacillus Tuberculosis).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
2. Event-free Survival (EFS) as assessed by Investigator

Secondary endpoints 9

1. pCR rate using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) at the time of definitive surgery
2. pCR rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery
3. EFS in participants with tumors expressing PD-L1
4. pCR rate using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) at the time of definitive surgery
5. Overall survival (OS)
6. Percentage of participants who experience an adverse event (AE)
7. Percentage of participants who discontinue study treatment due to an AE
8. European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score
9. EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Francisco Beca

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Francisco Beca

Third parties 9

Locations

8 EU/EEA countries · 51 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 65 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications