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Clinical Trial 20089

Cancer Type: Multiple
Study Type: Treatment
NCT#: NCT04042701

Phase: Phase I
Principal Investigator: Khong, Hung

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Study Title

A Phase 1b, Multicenter, Two-Part, Open label Study Of Trastuzumab Deruxtecan, 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)


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.


Study Objectives Primary Objectives - To determine the maximum tolerated dose/regimen (MTD) or the recommended dose for expansion (RDE) of DS-8201a when used in combination with pembrolizumab (Part 1) - To evaluate the efficacy of combination treatment with DS-8201a and pembrolizumab in human epidermal growth factor receptor-2 (HER2)-expressing locally advanced/metastatic breast cancer as well as HER2-expressing or HER2- mutant locally advanced/metastatic NSCLC (Part 2) Secondary Objectives - Key Secondary Objectives - To assess the safety and tolerability of the DS-8201a and pembrolizumab regimen - To determine the PK of DS-8201a when dosed in combination with pembrolizumab Other Secondary Objectives Not applicable. Exploratory Objectives - To analyze biomarkers related to the combination treatment - To understand the mechanism of response and resistance based on pretreatment, posttreatment, and on-treatment biopsies





DS-8201a (Trastuzumab Deruxtecan); Pembrolizumab (Keytruda); Trastuzumab Deruxtecan ()

Inclusion Criteria

Inclusion Criteria:

  • 18 years or older
  • 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
  • Male and female participants of reproductive potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug. Female subjects must not be pregnant or expect to conceive and must avoid breastfeeding for the same period of time. Male subjects must not expect to father a child for at least 4 months after the last dose of study drug(s).
  • Female participants must not donate or retrieve ova for their own use, from the time of Screening and throughout the study treatment period, and for at least 7 months after the last dose of study drug. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study. Inclusion Criteria Specific to Part 1
  • Participants in Part 1 should meet the additional inclusion criteria listed for 1 of the 4 BC or NSCLC 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 negative)
  • 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 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

    Exclusion Criteria:

  • Prior treatment with pembrolizumab or T-DXd
  • 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
  • Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
  • Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for subjects who are included in the study.
  • Uncontrolled infection requiring IV antibiotics, anti-virals, or anti-fungals

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