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

• ClinicalTrials.gov Identifier: NCT04042701
• Recruitment Status: Recruiting
• First Posted: August 2, 2019
• Last Update Posted: March 22, 2024
• Sponsor: Daiichi Sankyo
• Collaborators: AstraZeneca UK Limited; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: July 31, 2019
• First Posted Date: August 2, 2019
• Last Update Posted Date: March 22, 2024
• Actual Study Start Date: February 10, 2020
• Estimated Primary Completion Date: December 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 31, 2019)

• Dose-limiting toxicities (DLTs), Part 1 [ Time Frame: Within two 3-week cycles (6 weeks) ]
  Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.
• Objective Response Rate (ORR), Confirmed by Independent Central Review, Part 2 [ Time Frame: Within approximately 30 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 26, 2021)

• Treatment-emergent adverse events [ Time Frame: Within approximately 30 months ]
• Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) [ Time Frame: 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) ]
  Cmax of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.
• Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) [ Time Frame: 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) ]
  Area under the concentration-time curve of trastuzumab deruxtecan, MAAA-118A, and total anti-HER2 antibody will be assessed.
• Duration of Response (DoR) [ Time Frame: Within approximately 30 months ]
• Disease Control Rate (DCR) [ Time Frame: Within approximately 30 months ]
• Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1 [ Time Frame: Within approximately 30 months ]
• Time to Response (TTR), based on Independent Central Review using RECIST v1.1 [ Time Frame: Within approximately 30 months ]
• Overall survival (OS) [ Time Frame: Within approximately 30 months ]

Original Secondary Outcome Measures (submitted: July 31, 2019)

• Duration of Response (DoR) [ Time Frame: Within approximately 30 months ]
• Disease Control Rate (DCR) [ Time Frame: Within approximately 30 months ]
• Progression-Free Survival (PFS), based on Independent Central Review using RECIST v1.1 [ Time Frame: Within approximately 30 months ]
• Time to Response (TTR), based on Independent Central Review using RECIST v1.1 [ Time Frame: Within approximately 30 months ]
• Overall survival (OS) [ Time Frame: Within approximately 30 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase 1b, open-label, 2-part, multicenter, non-randomized, multiple-dose study

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Breast Cancer
• 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.

• 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.

• 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.

Study Arms

• Experimental: 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.
  Interventions:

  • Drug: Trastuzumab deruxtecan (DS-8201a)
  • Drug: Pembrolizumab
• Experimental: 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.
  Interventions:

  • Drug: Trastuzumab deruxtecan (DS-8201a)
  • Drug: Pembrolizumab
• Experimental: 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.
  Interventions:

  • Drug: Trastuzumab deruxtecan (DS-8201a)
  • Drug: Pembrolizumab
• Experimental: 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.
  Interventions:

  • Drug: Trastuzumab deruxtecan (DS-8201a)
  • Drug: Pembrolizumab
• Experimental: 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.
  Interventions:

  • Drug: Trastuzumab deruxtecan (DS-8201a)
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 4, 2020): 115
• Original Estimated Enrollment (submitted: July 31, 2019): 105
• Estimated Study Completion Date: August 1, 2025
• Estimated Primary Completion Date: December 1, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Daiichi Sankyo Contact for Clinical Trial Information; 908-992-6400; CTRinfo@dsi.com

Contact: AZ Breast Cancer Study Navigators; +1-877-400-4656; AstraZeneca@CareboxHealth.com

• Listed Location Countries: France, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04042701
• Other Study ID Numbers: DS8201-A-U106; 2018-002489-38 ( EudraCT Number ); KEYNOTE KN-797 ( Other Identifier: Merck Sharp & Dohme Corp )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current

Collaborators

• AstraZeneca UK Limited
• Merck Sharp & Dohme LLC

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: March 2024