Clinical trial NCT04042701: DS8201a and Pembrolizumab in Participants With Locally Advanced/Metastatic Breast or Non-Small Cell Lung Cancer
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Breast Cancer
Non-small Cell Lung Carcinoma
Keywords: Human epidermal receptor 2 positive
Human epidermal receptor 2
Non-small Cell Lung Carcinoma
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: AstraZeneca
name: Merck Sharp & Dohme LLC
First posted: 2019-08-02
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose study
Primary purpose: TREATMENT

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.

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

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

Primary outcomes:
measure: Dose-limiting toxicities (DLTs), Part 1
timeFrame: Within two 3-week cycles (6 weeks)
measure: Objective Response Rate (ORR), Confirmed by Independent Central Review, Part 2
timeFrame: Within approximately 30 months
Secondary outcomes:
measure: Treatment-emergent adverse events
timeFrame: Within approximately 30 months
measure: Pharmacokinetic Parameter Maximum Serum Concentration (Cmax)
timeFrame: 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)
measure: Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC)
timeFrame: 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)
measure: Duration of Response (DoR)
timeFrame: Within approximately 30 months
measure: Disease Control Rate (DCR)
timeFrame: Within approximately 30 months
measure: Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1
timeFrame: Within approximately 30 months
measure: Time to Response (TTR), based on Independent Central Review using RECIST v1.1
timeFrame: Within approximately 30 months
measure: Overall survival (OS)
timeFrame: Within approximately 30 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Univ. of Cali. San Francisco Medical Center
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida (Cbo)
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffit Cancer Center
state: Florida
city: Bethesda
country: United States
facility: Center for Cancer & Blood Disorders
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Siteman Cancer Center-Washington University
state: Missouri
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Tyler
country: United States
facility: Hope Cancer Center of East Texas
state: Texas
city: Bordeaux
country: France
facility: Institut Bergonie
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Marseille
country: France
facility: CHUTimone
city: Marsielle
country: France
facility: Institut PAOLI-CALMETTES
city: Poitiers
country: France
facility: CHU de Poitiers
city: Toulouse
country: France
facility: Univ. du Cancer de Toulouse
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: A Coruña
country: Spain
facility: Hospital Teresa Herrera (C.H.U.A.C)
city: Barcelona
country: Spain
facility: Inst. Oncologico Baselga Hospital Quiron
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i de Sant Pau
city: Las Palmas de Gran Canaria
country: Spain
facility: Hopital Universitario Insular de Gran Canaria
city: Madrid
country: Spain
facility: Hospital General Univ. Gregorio Marañon
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute (SCRI)
city: Manchester
country: United Kingdom
facility: The Christie NHS Fond. Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden Hosptial
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: