Clinical Trials /

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

NCT04042701

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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, In Subjects With Locally Advanced/Metastatic Breast Or Non-Small Cell Lung Cancer (NSCLC)

Clinical Trial IDs

  • ORG STUDY ID: DS8201-A-U106
  • SECONDARY ID: 2018-002489-38
  • NCT ID: NCT04042701

Conditions

  • Breast Cancer
  • Non-small Cell Lung Carcinoma

Interventions

DrugSynonymsArms
Trastuzumab deruxtecan (DS-8201a)HER2-positive breast cancer (Part 2 Dose Expansion)
Trastuzumab deruxtecan (DS-8201a)Part 1 (Dose Escalation)
PembrolizumabPart 1 (Dose Escalation)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1 (Dose Escalation)ExperimentalHER2-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.
  • Trastuzumab deruxtecan (DS-8201a)
  • Pembrolizumab
HER2-positive breast cancer (Part 2 Dose Expansion)ExperimentalHER2-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.
  • Trastuzumab deruxtecan (DS-8201a)
  • Pembrolizumab
HER2-low breast cancer (Part 2 Dose Expansion)ExperimentalHER2 low breast cancer participants with prior failed standard treatments who received DS8201a at the RDE in combination with pembrolizumab 200 mg.
  • Trastuzumab deruxtecan (DS-8201a)
  • Pembrolizumab
HER2-expressing NSCLC (Part 2 Dose Expansion)ExperimentalHER2-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.
  • Trastuzumab deruxtecan (DS-8201a)
  • Pembrolizumab
HER2-mutant NSCLC (Part 2 Dose Expansion)ExperimentalHER2-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.
  • Trastuzumab deruxtecan (DS-8201a)
  • Pembrolizumab

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
             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 available targeted therapies 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 within 6 months before enrollment,
             symptomatic congestive heart failure (New York Heart Association Class II to IV),
             troponin levels consistent with myocardial infarction as defined according to the
             manufacturer within 28 days prior to enrollment

          -  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

          -  Clinically significant corneal disease

          -  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 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

          -  Known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Participants with basal cell carcinoma of the skin, squamous
             cell carcinoma of the skin, contralateral breast cancer, or carcinoma in situ (eg,
             breast carcinoma, cervical cancer in situ) that have undergone potentially curative
             therapy are not excluded.

          -  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

          -  Uncontrolled infection requiring IV antibiotics, anti-virals, or anti-fungals
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicities (DLTs), Part 1
Time Frame:Within two 3-week cycles (6 weeks)
Safety Issue:
Description:Maximum Tolerated Dose (MTD) or recommended dose expansion (RDE) of DS-8201a (Part1) are based on the occurrence of DLTs.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Human epidermal receptor 2 positive
  • HER2
  • NSCLC

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