DS8201a and Pembrolizumab in Participants With Locally Advanced/Metastatic Breast or Non-Small Cell Lung Cancer

NCT ID: NCT04042701

Last Updated: 2025-11-18

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 115 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-10
• Study Completion Date: 2027-03-31

Brief Summary

This two-part study will include a dose escalation part to determine the recommended dose for expansion of DS8201a and pembrolizumab and a dose expansion part to evaluate efficacy, safety, and tolerability of the combination.

Detailed Description

This phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose study will evaluate DS-8201a in combination with pembrolizumab in participants with advanced/metastatic breast cancer or non-small cell lung cancer (NSCLC).

In the dose escalation part of the study, escalating doses of DS-8201a in combination with pembrolizumab will be assessed. DS-8201a and pembrolizumab 200 mg will be administered on Day 1 of every 21-day cycle. The initial dose administered for DS8201a will be 3.2 mg/kg Q3W. Escalation to the next dose (5.4 mg/kg Q3W) will be based on acceptable safety signals based on the earlier dose cohort.

Upon completion of dose escalation with the recommended dose of escalation (RDE) established, the dose expansion part of the study will begin. The dose expansion part will include 4 cohorts: Human epidermal growth factor receptor 2 (HER2+) breast cancer participants with prior ado-trastuzumab emtansine (T-DM1), HER2 low breast cancer participants with prior failed standard treatments, HER2-expressing NSCLC participants who have not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents, and HER2-mutant NSCLC participants who have not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents.

Conditions

Breast Cancer; Non-small Cell Lung Carcinoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1 (Dose Escalation)

HER2-positive breast cancer, HER2-low expressing breast cancer, HER2-expressing NSCLC, and HER2-mutant NSCLC participants who received escalating doses of DS8201a (initial dose 3.2 mg/kg Q3W) and pembrolizumab 200 mg.

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan (DS-8201a)

Intervention Type: DRUG

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin.

Pembrolizumab

Intervention Type: DRUG

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

HER2-positive breast cancer (Part 2 Dose Expansion)

HER2-positive breast cancer participants with prior ado-trastuzumab emtansine (T-DM1) with disease progression and who received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan (DS-8201a)

Intervention Type: DRUG

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.

Pembrolizumab

Intervention Type: DRUG

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

HER2-low breast cancer (Part 2 Dose Expansion)

HER2 low breast cancer participants with prior failed standard treatments who received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan (DS-8201a)

Intervention Type: DRUG

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.

Pembrolizumab

Intervention Type: DRUG

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

HER2-expressing NSCLC (Part 2 Dose Expansion)

HER2-expressing NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan (DS-8201a)

Intervention Type: DRUG

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.

Pembrolizumab

Intervention Type: DRUG

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

HER2-mutant NSCLC (Part 2 Dose Expansion)

HER2-mutant NSCLC participants who had not received any prior treatment with anti-PD-1, anti-PD-L1, or HER2 agents and received DS8201a at the RDE in combination with pembrolizumab 200 mg.

Group Type: EXPERIMENTAL

Trastuzumab deruxtecan (DS-8201a)

Intervention Type: DRUG

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.

Pembrolizumab

Intervention Type: DRUG

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

Interventions

Trastuzumab deruxtecan (DS-8201a)

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.

Intervention Type: DRUG

Trastuzumab deruxtecan (DS-8201a)

Part 1: Two dose levels of DS-8201a (3.2 mg/kg Q3W and 5.4 mg/kg Q3W via intravenous (IV) infusion will be administered for the dose escalation part of the study in combination with pembrolizumab.

Part 2: Once Part 1 of the study is complete and a RDE for DS-8201a has been established, Part 2 will begin.

Intervention Type: DRUG

Pembrolizumab

All participants will receive pembrolizumab (200 mg Q3W) via intravenous (IV) infusion prior to DS-8201a in Parts 1 and 2 of the study.

Intervention Type: DRUG

Other Intervention Names

KEYTRUDA®

Eligibility Criteria

Inclusion Criteria

• Written informed consent
• Adults ≥18 years
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1
• Pathologically documented HER2-expressing locally advanced/metastatic breast cancer, and HER2-expressing or HER2-mutant locally advanced/metastatic NSCLC
• Willing to provide a tumor biopsy during screening and during treatment
• Have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by the Investigator
• Adequate cardiac function, as defined by left ventricular ejection fraction (LVEF) ≥50% within 28 days before enrollment.
• Adequate organ function
• Adequate treatment washout period before enrollment

• Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-positive expression as per American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) Guidelines
• Received prior trastuzumab emtansine (T-DM1) therapy with documented progression

• Pathologically documented, locally advanced/metastatic breast cancer that has centrally determined HER2-low expression (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH-])
• Participants must have exhausted treatments that can confer any clinically meaningful benefit (eg, other therapies such as hormonal therapy for participants who are hormone receptor positive)

• Pathologically documented, locally advanced/metastatic NSCLC that has centrally or locally determined HER2-expression (IHC 1+, 2+, or 3+)
• Participants who have known epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment

• Pathologically documented, locally advanced/metastatic HER2-mutant NSCLC
• Participants who have known EGFR mutation, ALK, BRAF V600E mutation, or ROS1 fusion should have disease progression after treatment with at least one genomically-targeted therapy for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment

Exclusion Criteria

• Prior treatment with pembrolizumab or DS-8201a
• Medical history of myocardial infarction (MI) within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV). Participants with troponin levels above the upper limit of normal at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before enrollment to rule out MI
• Corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males)
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Spinal cord compression or clinically active central nervous system metastases
• Active, known or suspected autoimmune disease
• Condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment
• Prior therapy with an anti-PD-1 or anti-PD-L1 agent
• Prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE)
• Prior anti-HER2 therapy is not allowed for participants with HER2 low-expressing breast cancer or participants with NSCLC (Cohorts 2, 3, or 4). Prior treatment with pan-HER tyrosine kinase inhibitor is allowed.
• Prior systemic anticancer therapy, including investigational agents within 2 to 6 weeks prior to treatment
• Unresolved toxicities from previous anticancer therapy
• Live vaccine within 30 days prior to the first dose of study drug
• 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
• Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral breast cancer
• History of severe hypersensitivity reactions to other monoclonal antibodies and/or any of the study drug components
• Active infection requiring systemic therapy
• Known history of human immunodeficiency virus (HIV) infection
• Active hepatitis B or C virus infection
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, or any other reason the participant is found not appropriate to participate in the opinion of the treating Investigator
• Known psychiatric or substance abuse disorders
• Prior organ transplantation, including allogeneic stem cell transplantation
• Pregnant, breastfeeding, or planning to become pregnant
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
• Uncontrolled infection requiring IV antibiotics, anti-virals, or anti-fungals

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Daiichi Sankyo

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Global Clinical Leader

Role: STUDY_DIRECTOR

Daiichi Sankyo

Locations

Univ. of Cali. San Francisco Medical Center

San Francisco, California, United States

Yale Cancer Center

New Haven, Connecticut, United States

Cancer Specialists of North Florida (Cbo)

Jacksonville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Moffit Cancer Center

Tampa, Florida, United States

Center for Cancer & Blood Disorders

Bethesda, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Siteman Cancer Center-Washington University

St Louis, Missouri, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Hope Cancer Center of East Texas

Tyler, Texas, United States

Institut Bergonie

Bordeaux, , France

Centre Hospitalier Intercommunal de Créteil

Créteil, , France

CHUTimone

Marseille, , France

Institut PAOLI-CALMETTES

Marsielle, , France

CHU de Poitiers

Poitiers, , France

Univ. du Cancer de Toulouse

Toulouse, , France

Institut Gustave Roussy

Villejuif, , France

Hospital Teresa Herrera (C.H.U.A.C)

A Coruña, , Spain

Inst. Oncologico Baselga Hospital Quiron

Barcelona, , Spain

Hospital de la Santa Creu i de Sant Pau

Barcelona, , Spain

Hopital Universitario Insular de Gran Canaria

Las Palmas de Gran Canaria, , Spain

Hospital General Univ. Gregorio Marañon

Madrid, , Spain

MD Anderson Cancer Center

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Virgen Macarena

Seville, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

The Royal Marsden NHS Foundation Trust

London, , United Kingdom

Sarah Cannon Research Institute (SCRI)

London, , United Kingdom

The Christie NHS Fond. Trust

Manchester, , United Kingdom

Royal Marsden Hosptial

Sutton, , United Kingdom

Countries

United States; France; Spain; United Kingdom

Other Identifiers

2018-002489-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

KEYNOTE-797

Identifier Type: OTHER

Identifier Source: secondary_id

MK-3475-797

Identifier Type: OTHER

Identifier Source: secondary_id

DS8201-A-U106

Identifier Type: -

Identifier Source: org_study_id