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

Breast Cancer Clinical Trial

Official title:

A Phase 1b, Multicenter, Two-Part, Open-Label Study of Trastuzumab Deruxtecan (DS-8201a), An Anti-Human Epidermal Growth Factor Receptor-2 (HER2)-Antibody Drug Conjugate (ADC), In Combination With Pembrolizumab, An Anti-PD-1 Antibody, For Subjects With Locally Advanced/Metastatic Breast Or Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04042701
• Other study ID #: DS8201-A-U106
• Secondary ID: 2018-002489-38KE
• Status: Recruiting
• Phase: Phase 1
• Start date: February 10, 2020
• Est. completion date: August 1, 2025

Study information

• Verified date: May 2024
• Source: Daiichi Sankyo
• Contact: Daiichi Sankyo Contact for Clinical Trial Information
• Phone: 908-992-6400
• Email: CTRinfo[@]dsi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 115
• Est. completion date: August 1, 2025
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Inclusion Criteria Specific to Part 1

• Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 cohorts in Part 2.

Inclusion Criteria Specific to Part 2

Inclusion Criteria for Cohort 1

• 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

Inclusion Criteria for Cohort 2

• 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)

Inclusion Criteria for Cohort 3

• 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

Inclusion Criteria for Cohort 4

• 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

Related Conditions & MeSH terms

• Breast Cancer
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Carcinoma

Intervention

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. All participants will receive DS-8201a at the RDE in combination with pembrolizumab.
• 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.
• 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.

Locations

Country	Name	City	State
France	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
Spain	Hospital Teresa Herrera (C.H.U.A.C)	A Coruña
Spain	Hospital de la Santa Creu i de Sant Pau	Barcelona
Spain	Inst. Oncologico Baselga Hospital Quiron	Barcelona
Spain	Hopital Universitario Insular de Gran Canaria	Las Palmas de Gran Canaria
Spain	Hospital General Univ. Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Sarah Cannon Research Institute (SCRI)	London
United Kingdom	The Royal Marsden NHS Foundation Trust	London
United Kingdom	The Christie NHS Fond. Trust	Manchester
United Kingdom	Royal Marsden Hosptial	Sutton
United Kingdom	Clatterbridge Cancer Centre	Wirral
United States	Center for Cancer & Blood Disorders	Bethesda	Maryland
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Cancer Specialists of North Florida (Cbo)	Jacksonville	Florida
United States	Yale Cancer Center	New Haven	Connecticut
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Siteman Cancer Center-Washington University	Saint Louis	Missouri
United States	Univ. of Cali. San Francisco Medical Center	San Francisco	California
United States	Moffit Cancer Center	Tampa	Florida
United States	Hope Cancer Center of East Texas	Tyler	Texas

Sponsors (3)

Lead Sponsor	Collaborator
Daiichi Sankyo	AstraZeneca UK Limited, Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  France,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-limiting toxicities (DLTs), Part 1	Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.	Within two 3-week cycles (6 weeks)
Primary	Objective Response Rate (ORR), Confirmed by Independent Central Review, Part 2		Within approximately 30 months
Secondary	Treatment-emergent adverse events		Within approximately 30 months
Secondary	Pharmacokinetic Parameter Maximum Serum Concentration (Cmax)	Cmax of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.	Cycle 1, Day 1: predose and postdose, Day 8, and Day 15; Cycle 2, Day 1 predose and postdose, and Cycle 3, Day 1 (each cycle is 21 days)
Secondary	Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC)	Area under the concentration-time curve of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.	Cycle 1, Day 1: predose and postdose, Day 8, and Day 15; Cycle 2, Day 1 predose and postdose, and Cycle 3, Day 1 (each cycle is 21 days)
Secondary	Duration of Response (DoR)		Within approximately 30 months
Secondary	Disease Control Rate (DCR)		Within approximately 30 months
Secondary	Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1		Within approximately 30 months
Secondary	Time to Response (TTR), based on Independent Central Review using RECIST v1.1		Within approximately 30 months
Secondary	Overall survival (OS)		Within approximately 30 months