<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04420598</url>
  </required_header>
  <id_info>
    <org_study_id>MEDOPP243</org_study_id>
    <secondary_id>2019-001739-29</secondary_id>
    <nct_id>NCT04420598</nct_id>
  </id_info>
  <brief_title>DS-8201a for trEatment of aBc, BRain Mets, And Her2[+] Disease</brief_title>
  <acronym>DEBBRAH</acronym>
  <official_title>Multicenter, Open-Label, Single-Arm, Multicohort Phase II Clinical Trial of Trastuzumab Deruxtecan(DS-8201a) in Human Epidermal Growth Factor Receptor 2 HER2+ Advanced Breast Cancer With Brain Metastases and/or Leptomeningeal Carcinomatosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MedSIR</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Daiichi Sankyo, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>MedSIR</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal&#xD;
      Simon's design, phase II clinical trial&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pretreated, unresectable locally advanced or metastatic Human Epidermal Growth Factor&#xD;
      Receptor 2 (HER2)-positive or HER2-low expressing breast cancer (BC) with untreated or&#xD;
      treated brain metastases (BMs) or leptomeningeal carcinomatosis (LMC).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 25, 2020</start_date>
  <completion_date type="Actual">April 4, 2023</completion_date>
  <primary_completion_date type="Actual">September 30, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon's design, phase II clinical trial.&#xD;
After confirmed eligibility, patients will be assigned to one of the following five study cohorts:&#xD;
Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);&#xD;
Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;&#xD;
Cohort 3: HER2-positive BC with progressing BMs after local treatment;&#xD;
Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;&#xD;
Cohort 5: HER2-positive or HER2-low expressing BC with LMC</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cohort 1, asses efficacy, defined as 16 weeks progression-free survival (PFS) of DS8201a</measure>
    <time_frame>Baseline up to 16 weeks</time_frame>
    <description>To assess efficacy -defined as 16 weeks progression-free survival (PFS)- per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery). 16 weeks-PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first during at least first 6 months. Progression will be determined locally by the investigator through the use of Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria for intracranial (IC) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cohort 2, 3 and 4, asses efficacy defined as ORR-IC (DS-8201a)</measure>
    <time_frame>From 16 weeks up tp 14 month</time_frame>
    <description>To assess efficacy -defined as intracranial overall response rate (ORR-IC) per RANO-BM of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic BC:&#xD;
HER2-positive or HER2-low expressing with untreated BMs (Cohort 2);&#xD;
HER2-positive with progressing BMs after local treatment (Cohort 3);&#xD;
HER2-low expressing with progressing BMs after local treatment (Cohort 4).&#xD;
ORR-IC, defined as a complete response (CR) or partial response (PR), and determined locally by the investigator through the use of RANO-BM criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cohort 5 asses efficacy,defined as OS of DS-8201a</measure>
    <time_frame>From 16 weeks up tp 14 month</time_frame>
    <description>To assess efficacy -defined as OS- of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive or HER2-low expressing BC with LMCOS defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cohort 1 to assess efficacy -defined as ORR</measure>
    <time_frame>From 16 weeks up tp 14 month</time_frame>
    <description>ORR, defined as a complete response (CR) or partial response (PR), determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v. 1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1 to assess efficacy -defined as CBR</measure>
    <time_frame>From 16 weeks up tp 14 month</time_frame>
    <description>CBR, defined as an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1 to assess efficacy -defined as TTR</measure>
    <time_frame>From 16 weeks up tp 14 month</time_frame>
    <description>TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1 to assess efficacy -defined as DoR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1 to assess efficacy -defined as OS</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1: To assess efficacy -defined as PFS-</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1: to assess efficacy -defined as best percentage of change</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Best percentage of change from baseline in the size of CNS lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through use of RANO-BM criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 1, To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population.</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Patient safety and adverse events (AEs) will be evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4: To assess efficacy -defined as 6-month PFS</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as ORR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>ORR, defined as a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as CBR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as TTR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>TTR, defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as DOR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as OS</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4. To asses efficacy -defined as best percentage of change</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, . To asses efficacy -defined as time to WBR and/or SRS</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Time to WBR and/or SRS (only for cohort 2), defined as the time from the treatment initiation to time of CNS disease progression that requires treatment with WBR and/or SRS, and determined locally by the investigator through the use of RANO-BM criteria and RECIST criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort 2, 3 and 4.To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a)</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0. All AEs and SAEs will be assessed to determine the safety and tolerability of the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as ORR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>CNS ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as PFS</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as CBR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as TTR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as DOR</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess efficacy -defined as best percentage of change</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cohort5, To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population.</measure>
    <time_frame>From 16 weeks up to 14 months</time_frame>
    <description>Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0. All AEs and SAEs will be assessed to determine the safety and tolerability of the treatment.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To assess patient reported outcomes (PROs) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23 in this population.</measure>
    <time_frame>Baseline up to 18 months</time_frame>
    <description>Overall change from baseline in patient-reported global health status/quality of life (GHS/QoL), functioning and symptoms; Time to deterioration in global QoL; Time to deterioration in pain; Time to next therapy.</description>
  </other_outcome>
  <other_outcome>
    <measure>To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) associated with disease activity status or response to treatment in this population.</measure>
    <time_frame>Baseline up to 18 months</time_frame>
    <description>Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical characteristics (e.g., baseline features) and outcome (e.g., duration of PFS).</description>
  </other_outcome>
  <other_outcome>
    <measure>To identify possible mechanisms of resistance to study treatments through the comparative analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood and/or CSF samples from this population.</measure>
    <time_frame>Baseline up to 18 months</time_frame>
    <description>Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical characteristics (e.g., baseline features) and outcome (e.g., duration of PFS).</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Advanced Breast Cancer</condition>
  <condition>HER2-positive Breast Cancer</condition>
  <condition>Brain Metastases</condition>
  <condition>Leptomeningeal Metastasis</condition>
  <arm_group>
    <arm_group_label>Trastuzumab deruxtecan (DS-8201a)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);&#xD;
Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;&#xD;
Cohort 3: HER2-positive BC with progressing BMs after local treatment;&#xD;
Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;&#xD;
Cohort 5: HER2-positive or HER2-low expressing BC with LMC.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trastuzumab deruxtecan</intervention_name>
    <description>After having confirmed eligibility and entered into the clinical trial, patients will be treated with trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an intravenous (IV) infusion on Day of 21-day cycle (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes.&#xD;
In patients with hormone receptor (HR)-positive status (estrogen receptor [ER] and/or progesterone receptor [PgR]) administration of endocrine therapy is not allowed.&#xD;
In patients allocated in study cohort 5, administration of intrathecal therapy is not allowe</description>
    <arm_group_label>Trastuzumab deruxtecan (DS-8201a)</arm_group_label>
    <other_name>(DS-8201a)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed Informed Consent Form (ICF) prior to participation in any study-related&#xD;
             activities.&#xD;
&#xD;
          2. Male or female patients ≥ 18 years at the time of signing ICF.&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for Cohorts 1 to 4&#xD;
             and 0-2 for cohort 5.&#xD;
&#xD;
          4. Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          5. Histologically confirmed invasive breast cancer based on local testing on the most&#xD;
             recent analyzed biopsy of the following breast cancer (BC) subtypes per 2018 American&#xD;
             Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria:&#xD;
&#xD;
               -  Cohort 1 and 3: HER2 positive status&#xD;
&#xD;
               -  Cohort 4: HER2-low expressing status&#xD;
&#xD;
               -  Cohort 2 and 5: both HER2 positive and HER2-low expressing status&#xD;
&#xD;
             Note 1: According to the 2018 ASCO-CAP guidelines, HER2- positive status is defined as&#xD;
             HER2 immunohistochemistry (IHC) 3+, in situ hybridization (ISH) ≥ 2.0, or average HER2&#xD;
             copy number ≥ 6.0 signals. HER2-low expressing status defined as IHC 2+ / ISH-negative&#xD;
             or IHC 1+ (ISH-negative or untested).&#xD;
&#xD;
             Note 2: Central confirmation of HER2 is not required for study entry. However, tissue&#xD;
             blocks, or slides, must be submitted to confirm BC subtype by a Sponsor-designated&#xD;
             central laboratory retrospectively.&#xD;
&#xD;
          6. Unresectable locally advanced or metastatic disease documented by computerized&#xD;
             tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to&#xD;
             resection with curative intent.&#xD;
&#xD;
          7. At least one brain lesion needed to be measurable (≥10 mm on T1-weighted,&#xD;
             gadolinium-enhanced MRI) (study cohorts 2 to 4) or leptomeningeal carcinomatosis (LMC)&#xD;
             with positive cerebrospinal fluid (CSF) cytology (study cohort 5).&#xD;
&#xD;
               -  Study cohort 1: History of BM that are non-progressing after WBRT and/or SRS and&#xD;
                  or surgery.&#xD;
&#xD;
               -  Study cohort 2: Presence of asymptomatic BM without clinical requirement for&#xD;
                  local intervention (WBRT and/or SRS and/or surgery).&#xD;
&#xD;
               -  Study cohorts 3 and 4: Evidence of new and/or progressive BM following previous&#xD;
                  WBRT and/or SRS and/or surgery.&#xD;
&#xD;
               -  Study cohort 5: Evidence of LMC with positive CSF cytology.&#xD;
&#xD;
          8. Previous treatments:&#xD;
&#xD;
               -  For HER2-positive patients have been previously treated with a taxane and at&#xD;
                  least one HER2-targeted therapy in the advanced scenario.&#xD;
&#xD;
               -  For HER2-low-expressing patients that also are endocrine receptor negative must&#xD;
                  have been previously treated with at least one chemotherapy regimen. If endocrine&#xD;
                  receptor positive, patients must have been previously treated with at least one&#xD;
                  chemotherapy and one endocrine regimen in the metastatic setting.&#xD;
&#xD;
          9. Patients must agree to collection of blood samples at the time of inclusion, at cycle&#xD;
             2 of treatment, and upon progression or study termination.&#xD;
&#xD;
             Note: In study cohort 5: Patients must agree to perform spinal taps or must be willing&#xD;
             to have an Ommaya reservoir placed for CSF assessment, at baseline, every three weeks&#xD;
             for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks&#xD;
             thereafter.&#xD;
&#xD;
         10. Willingness and ability to provide tumor biopsy (if feasible) from metastatic lesions&#xD;
             or breast primary tumor both at the time of the inclusion and after disease&#xD;
             progression in order to perform exploratory studies.&#xD;
&#xD;
             Note: If feasible, patients should provide a tissue sample at baseline from metastases&#xD;
             amenable to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or&#xD;
             lymph nodes], or distant recurrence [bone, liver, lung or abdomen]) or as alternative&#xD;
             from breast primary tumor, that will be obtained between progression to the prior&#xD;
             regimen and inclusion in the study. Patients for whom tissue sample cannot be obtained&#xD;
             (e.g., non-measurable disease, inaccessible tumor or subject safety concern) may&#xD;
             submit an archived metastatic tumor specimen only upon agreement from the Sponsor. If&#xD;
             feasible, an additional tissue sample should be collected at the end of treatment&#xD;
             visit for patients who discontinue treatment due to disease progression.&#xD;
&#xD;
         11. Patients should have left ventricular ejection fraction (LVEF) ≥ 50% by either an&#xD;
             echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before&#xD;
             enrolment.&#xD;
&#xD;
         12. Adequate hematologic and organ function within 14 days before the first study&#xD;
             treatment on Day 1 of Cycle 1, defined by the following:&#xD;
&#xD;
             • Hematological: White blood cell (WBC) count 3 3.0 x 109/L, absolute neutrophil count&#xD;
             (ANC) 3 1.5 x 109/L, platelet count 3 100.0 x109/L, and hemoglobin 3 9.0 g/dL.&#xD;
             (Platelet, red blood cell transfusion as well as G-CSF administration are not allowed&#xD;
             within 1 week of screening assessments).&#xD;
&#xD;
             Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (&lt; 3 x ULN in the&#xD;
             case of documented Gilbert's disease and/or liver metastases); aspartate transaminase&#xD;
             (AST) and alanine transaminase (ALT) ≤ 3 × ULN (in the case of liver metastases ≤ 5 ×&#xD;
             ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN in the case of liver and/or bone&#xD;
             metastases ≤ 5 × ULN), serum albumin 3 2.5 g/dL&#xD;
&#xD;
             • Renal: Serum creatinine £ 1.5 × ULN or creatinine clearance ≥ 30 mL/min based on&#xD;
             Cockcroft-Gault equation (*Cockcroft-Gault equation: ([{140 - age in years} × {ACTUAL&#xD;
             WEIGHT in kg}] divided by [{72 × serum creatinine in mg/dL} multiplied by 0.85 if&#xD;
             female])) Coagulation: International Normalized Ratio (INR)/Prothrombin Time (PT) and&#xD;
             activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN (except for patients&#xD;
             receiving anticoagulation therapy).&#xD;
&#xD;
             Note: Patients receiving heparin treatment should have an aPTT) between 1.5 and 2.5 ×&#xD;
             ULN (or patient value before starting heparin treatment). Patients receiving coumarin&#xD;
             derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive&#xD;
             measurements one to four days apart. Patients should be on a stable anticoagulant&#xD;
             regimen.&#xD;
&#xD;
         13. Has adequate treatment washout period before enrollment, as indicated:&#xD;
&#xD;
               1. Major surgery: &gt; 4 weeks;&#xD;
&#xD;
               2. Radiation therapy: &gt; 4 weeks (palliative stereotactic radiation therapy to other&#xD;
                  areas ≥ 2 weeks);&#xD;
&#xD;
               3. Anticancer systemic treatment (including immunotherapy, retinoid therapy,&#xD;
                  hormonal therapy): ≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer, for&#xD;
                  small-molecule targeted agents such as 5-fluorouracil-based agents, folinate&#xD;
                  agents, weekly paclitaxel; ≥ 6 weeks for nitrosureas or mitomycin C);&#xD;
&#xD;
               4. Antibody based anti-cancer therapy:≥ 4 weeks;&#xD;
&#xD;
               5. Chloroquine/Hydroxychloroquine&gt;14 days&#xD;
&#xD;
         14. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤1 as&#xD;
             determined by the National Cancer Institute-Common Terminology Criteria for Adverse&#xD;
             Events (NCI-CTCAE) v.5.0 (except for alopecia or other toxicities). Subjects with&#xD;
             chronic Grade 2 toxicities may be eligible per the discretion of the Investigator&#xD;
             after consultation with the Sponsor Medical Monitor or designee (e.g., Grade 2&#xD;
             chemotherapy-induced neuropathy).&#xD;
&#xD;
         15. Male and female subjects of reproductive/childbearing potential must agree to use a&#xD;
             highly effective form of contraception or avoid intercourse during and upon completion&#xD;
             of the study and for at least 7 months for females and 4 months for males after the&#xD;
             last dose of study drug. Methods considered as highly effective methods of&#xD;
             contraception include:&#xD;
&#xD;
               -  Combined (estrogen and progestogen containing) hormonal contraception associated&#xD;
                  with inhibition of ovulation:&#xD;
&#xD;
                  i. Oral ii. Intravaginal iii. Transdermal&#xD;
&#xD;
               -  Progestogen-only hormonal contraception associated with inhibition of ovulation:&#xD;
                  iv. Oral v. Injectable vi. Implantable&#xD;
&#xD;
               -  Intrauterine device (IUD)&#xD;
&#xD;
               -  Intrauterine hormone-releasing system (IUS)&#xD;
&#xD;
               -  Bilateral tubal occlusion&#xD;
&#xD;
               -  Vasectomized partner&#xD;
&#xD;
               -  Complete sexual abstinence defined as refraining from heterosexual intercourse&#xD;
                  during and upon completion of the study and for at least 7 months after the last&#xD;
                  dose of study drug. Periodic abstinence (calendar, symptothermal, post-ovulation&#xD;
                  methods) is not an acceptable method of contraception.&#xD;
&#xD;
             Note: Non-child-bearing potential defined as pre-menopausal females with a documented&#xD;
             tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous&#xD;
             amenorrhea (in questionable cases, a blood sample with simultaneous&#xD;
             follicle-stimulating hormone [FSH] &gt; 40 mIU/mL and estradiol &lt; 40 pg/mL [&lt; 147 pmol/L]&#xD;
             is confirmatory).&#xD;
&#xD;
         16. Male subjects must agree to not freeze or donate sperm starting at Screening and&#xD;
             throughout the study period, and at least 7months after the final study drug&#xD;
             administration. Preservation of sperm should be considered prior to enrolment in this&#xD;
             study.&#xD;
&#xD;
         17. Female subjects must agree to not donate, or retrieve for their own use, ova from the&#xD;
             time of Screening and throughout the study treatment period, and for at least 7 months&#xD;
             after the final study drug administration.&#xD;
&#xD;
         18. Patients who are willing and able to comply with scheduled visits, treatment plan,&#xD;
             laboratory tests, post-treatment follow-up and other study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients will be excluded from the study if they meet ANY of the following criteria:&#xD;
&#xD;
          1. Inability to comply with study and follow-up procedures.&#xD;
&#xD;
          2. Previous treatment with trastuzumab deruxtecan (DS-8201a) or any other antibody drug&#xD;
             conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase 1&#xD;
             inhibitor.&#xD;
&#xD;
          3. Medical history of myocardial infarction within 6 months before enrollment,&#xD;
             symptomatic congestive heart failure (New York Heart Association Class II to IV),&#xD;
             troponin levels consistent with myocardial infarction within 28 days prior to&#xD;
             enrollment.&#xD;
&#xD;
          4. Corrected QT interval (QTc) prolongation to &gt; 470 ms (females) or &gt;450 ms (males)&#xD;
             based on average of the screening triplicate12- lead ECG.&#xD;
&#xD;
          5. History of (non-infectious) interstitial lung disease (ILD) that required steroids,&#xD;
             has current ILD, or where suspected ILD cannot be ruled out by imaging at screening.&#xD;
&#xD;
          6. Clinically significant corneal disease in the opinion of the Investigator.&#xD;
&#xD;
          7. Spinal cord compression.&#xD;
&#xD;
          8. Multiple primary malignancies within 3 years, except adequately resected non-melanoma&#xD;
             skin cancer, curatively treated in-situ disease, other solid tumors curatively&#xD;
             treated, or contralateral breast cancer.&#xD;
&#xD;
          9. History of severe hypersensitivity reactions to either the drug substances or inactive&#xD;
             ingredients in the drug product.&#xD;
&#xD;
         10. History of severe hypersensitivity reactions to other monoclonal antibodies.&#xD;
&#xD;
         11. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.&#xD;
&#xD;
         12. Patients with substance abuse or any other medical conditions such as clinically&#xD;
             significant cardiac or psychological conditions, that may, in the opinion of the&#xD;
             investigator, interfere with the subject's participation in the clinical study or&#xD;
             evaluation of the clinical study results.&#xD;
&#xD;
         13. Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C&#xD;
             infection. Subjects should be tested for HIV prior to enrollment if required by local&#xD;
             regulations or institutional review board (IRB)/ethics committee (EC).&#xD;
&#xD;
         14. Female patients who are pregnant or breastfeeding or planning to become pregnant.&#xD;
&#xD;
         15. No other systemic therapy for metastatic disease including chemotherapy,&#xD;
             immunotherapy, targeted therapy (small molecules/ monoclonal antibodies), or endocrine&#xD;
             therapy&#xD;
&#xD;
         16. Major surgery (defined as requiring general anesthesia) or significant traumatic&#xD;
             injury within 4 weeks of start of study drug, or patients who have not recovered from&#xD;
             the side effects of any major surgery, or patients who may require major surgery&#xD;
             during the study.&#xD;
&#xD;
         17. Radiotherapy within 4 weeks or limited-field palliative radiotherapy within 2 weeks&#xD;
             prior to study enrolment, or patients who have not recovered from radiotherapy-related&#xD;
             toxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow has been&#xD;
             previously irradiated.&#xD;
&#xD;
         18. Use of concurrent investigational agents or other concomitant anticancer therapies.&#xD;
&#xD;
         19. Use of intrathecal therapy for LMC&#xD;
&#xD;
         20. Active bleeding diathesis, previous history of bleeding diathesis, or chronic&#xD;
             anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon&#xD;
             as it is used as prophylaxis intention).&#xD;
&#xD;
         21. Serious concomitant systemic disorder (e.g., active infection including HIV, active&#xD;
             hepatitis, liver cirrhosis, end stage chronic renal disease) incompatible with the&#xD;
             study (at the discretion of investigator).&#xD;
&#xD;
         22. Any of the following within 6 months of enrollment: severe/unstable angina, ongoing&#xD;
             cardiac dysrhythmias of NCI-CTCAE v.5.0 grade 32, coronary/peripheral artery bypass&#xD;
             graft, cerebrovascular accident including transient ischemic attack, or symptomatic&#xD;
             pulmonary embolism.&#xD;
&#xD;
         23. Uncontrolled electrolyte disorders of NCI-CTCAE v.5.0 grade ≥ 2.&#xD;
&#xD;
         24. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses&#xD;
             including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary&#xD;
             emboli within three months of the study enrollment, severe asthma, severe COPD,&#xD;
             restrictive lung disease, pleural effusion etc.), and any autoimmune, connective&#xD;
             tissue or inflammatory disorders with potential pulmonary involvement (i.e. Rheumatoid&#xD;
             arthritis, Sjogren's, sarcoidosis etc.), or prior pneumonectomy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marta Vaz Batista, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>MedSIR</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Champalimaud Center for the Unknown</name>
      <address>
        <city>Lisbon</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Português de Oncologia do Porto Francisco Gentil, EPE (IPO Porto)</name>
      <address>
        <city>Porto</city>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologica ICO Badalona</name>
      <address>
        <city>Badalona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Dexeus</name>
      <address>
        <city>Barcelona</city>
        <zip>08028</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital del Mar</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Oncologic Baselga-Hospital Quiron Salud Barcelona</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Reina Sofia</name>
      <address>
        <city>Córdoba</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Catala d'Oncologia ICO Hospitalet</name>
      <address>
        <city>L'Hospitalet De Llobregat</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico San Carlos</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IOB- Complejo Hospitalario Ruber Juan Bravo</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocio</name>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fundación Instituto Valenciano de Oncología (IVO)</name>
      <address>
        <city>Valencia</city>
        <zip>46009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Migue Servet</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Portugal</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>May 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Breast cancer</keyword>
  <keyword>HER2</keyword>
  <keyword>Brain metastases</keyword>
  <keyword>Metastatic</keyword>
  <keyword>unrescatable</keyword>
  <keyword>pretreated</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Neoplasms, Second Primary</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Trastuzumab deruxtecan</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04420598
org study id: MEDOPP243
secondary id: 2019-001739-29
nct id: NCT04420598
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal
      Simon's design, phase II clinical trial
Pretreated, unresectable locally advanced or metastatic Human Epidermal Growth Factor
      Receptor 2 (HER2)-positive or HER2-low expressing breast cancer (BC) with untreated or
      treated brain metastases (BMs) or leptomeningeal carcinomatosis (LMC).
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a multicenter, international, open-label, single-arm, multicohort, two-stage optimal Simon's design, phase II clinical trial.
After confirmed eligibility, patients will be assigned to one of the following five study cohorts:
Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);
Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;
Cohort 3: HER2-positive BC with progressing BMs after local treatment;
Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;
Cohort 5: HER2-positive or HER2-low expressing BC with LMC
primary purpose: Treatment
masking: None (Open Label)
measure: Cohort 1, asses efficacy, defined as 16 weeks progression-free survival (PFS) of DS8201a
time frame: Baseline up to 16 weeks
description: To assess efficacy -defined as 16 weeks progression-free survival (PFS)- per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery). 16 weeks-PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first during at least first 6 months. Progression will be determined locally by the investigator through the use of Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria for intracranial (IC) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4, asses efficacy defined as ORR-IC (DS-8201a)
time frame: From 16 weeks up tp 14 month
description: To assess efficacy -defined as intracranial overall response rate (ORR-IC) per RANO-BM of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic BC:
HER2-positive or HER2-low expressing with untreated BMs (Cohort 2);
HER2-positive with progressing BMs after local treatment (Cohort 3);
HER2-low expressing with progressing BMs after local treatment (Cohort 4).
ORR-IC, defined as a complete response (CR) or partial response (PR), and determined locally by the investigator through the use of RANO-BM criteria.
measure: Cohort 5 asses efficacy,defined as OS of DS-8201a
time frame: From 16 weeks up tp 14 month
description: To assess efficacy -defined as OS- of trastuzumab deruxtecan (DS-8201a) in patients with pretreated unresectable locally advanced or metastatic HER2-positive or HER2-low expressing BC with LMCOS defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up
measure: Cohort 1 to assess efficacy -defined as ORR
time frame: From 16 weeks up tp 14 month
description: ORR, defined as a complete response (CR) or partial response (PR), determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v. 1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 1 to assess efficacy -defined as CBR
time frame: From 16 weeks up tp 14 month
description: CBR, defined as an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 1 to assess efficacy -defined as TTR
time frame: From 16 weeks up tp 14 month
description: TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 1 to assess efficacy -defined as DoR
time frame: From 16 weeks up to 14 months
description: DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 1 to assess efficacy -defined as OS
time frame: From 16 weeks up to 14 months
description: OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up.
measure: Cohort 1: To assess efficacy -defined as PFS-
time frame: Through study completion, an average of 1 year
description: PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 1: to assess efficacy -defined as best percentage of change
time frame: From 16 weeks up to 14 months
description: Best percentage of change from baseline in the size of CNS lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through use of RANO-BM criteria.
measure: Cohort 1, To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population.
time frame: From 16 weeks up to 14 months
description: Patient safety and adverse events (AEs) will be evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. All AEs and serious adverse events (SAEs) will be assessed to determine the safety and tolerability of the treatment.
measure: Cohort 2, 3 and 4: To assess efficacy -defined as 6-month PFS
time frame: From 16 weeks up to 14 months
description: PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4. To asses efficacy -defined as ORR
time frame: From 16 weeks up to 14 months
description: ORR, defined as a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4. To asses efficacy -defined as CBR
time frame: From 16 weeks up to 14 months
description: CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4. To asses efficacy -defined as TTR
time frame: From 16 weeks up to 14 months
description: TTR, defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4. To asses efficacy -defined as DOR
time frame: From 16 weeks up to 14 months
description: DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, 3 and 4. To asses efficacy -defined as OS
time frame: From 16 weeks up to 14 months
description: OS, defined as the time from treatment initiation to death from any cause. Patients without documented death at the time of the final analysis will be censored at the date of the last follow-up
measure: Cohort 2, 3 and 4. To asses efficacy -defined as best percentage of change
time frame: From 16 weeks up to 14 months
description: Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort 2, . To asses efficacy -defined as time to WBR and/or SRS
time frame: From 16 weeks up to 14 months
description: Time to WBR and/or SRS (only for cohort 2), defined as the time from the treatment initiation to time of CNS disease progression that requires treatment with WBR and/or SRS, and determined locally by the investigator through the use of RANO-BM criteria and RECIST criteria.
measure: Cohort 2, 3 and 4.To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a)
time frame: From 16 weeks up to 14 months
description: Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0. All AEs and SAEs will be assessed to determine the safety and tolerability of the treatment.
measure: Cohort5, To assess efficacy -defined as ORR
time frame: From 16 weeks up to 14 months
description: CNS ORR, defined as a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort5, To assess efficacy -defined as PFS
time frame: From 16 weeks up to 14 months
description: PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort5, To assess efficacy -defined as CBR
time frame: From 16 weeks up to 14 months
description: CBR, defined as an objective response (CR or PR), or SD for at least 24 weeks, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort5, To assess efficacy -defined as TTR
time frame: From 16 weeks up to 14 months
description: TTR, defined as the time from the treatment initiation to time of the first objective tumor response observed for patients who achieved a CR or PR, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort5, To assess efficacy -defined as DOR
time frame: From 16 weeks up to 14 months
description: DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions.
measure: Cohort5, To assess efficacy -defined as best percentage of change
time frame: From 16 weeks up to 14 months
description: Best percentage of change from baseline in the size of tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, and determined locally by the investigator through the use of RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both extracranial lesions and overall (IC and extracranial) lesions
measure: Cohort5, To assess the safety and tolerability of trastuzumab deruxtecan (DS-8201a) in this population.
time frame: From 16 weeks up to 14 months
description: Patient safety and AEs will be evaluated using the NCI-CTCAE v.5.0. All AEs and SAEs will be assessed to determine the safety and tolerability of the treatment.
measure: To assess patient reported outcomes (PROs) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23 in this population.
time frame: Baseline up to 18 months
description: Overall change from baseline in patient-reported global health status/quality of life (GHS/QoL), functioning and symptoms; Time to deterioration in global QoL; Time to deterioration in pain; Time to next therapy.
measure: To evaluate predictive or prognostic biomarkers (plasma and/or tissue and/or CSF) associated with disease activity status or response to treatment in this population.
time frame: Baseline up to 18 months
description: Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical characteristics (e.g., baseline features) and outcome (e.g., duration of PFS).
measure: To identify possible mechanisms of resistance to study treatments through the comparative analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood and/or CSF samples from this population.
time frame: Baseline up to 18 months
description: Relationship between tissue- and/or blood- and/or CSF-based biomarkers and patient clinical characteristics (e.g., baseline features) and outcome (e.g., duration of PFS).
arm group label: Trastuzumab deruxtecan (DS-8201a)
arm group type: Experimental
description: Cohort 1: HER2-positive BC with non-progressing BM (after WBRT and/or SRS and or surgery.);
Cohort 2: HER2-positive or HER2-low BC with asymptomatic untreated BM;
Cohort 3: HER2-positive BC with progressing BMs after local treatment;
Cohort 4: HER2-low expressing BC with progressing BMs after local treatment;
Cohort 5: HER2-positive or HER2-low expressing BC with LMC.
intervention type: Drug
intervention name: Trastuzumab deruxtecan
description: After having confirmed eligibility and entered into the clinical trial, patients will be treated with trastuzumab deruxtecan (DS-8201a) at 5.4 mg/Kg administered as an intravenous (IV) infusion on Day of 21-day cycle (Q3W), initially for at least 90 minutes, then, if there is no infusion-related reaction, for a minimum of 30 minutes.
In patients with hormone receptor (HR)-positive status (estrogen receptor [ER] and/or progesterone receptor [PgR]) administration of endocrine therapy is not allowed.
In patients allocated in study cohort 5, administration of intrathecal therapy is not allowe
arm group label: Trastuzumab deruxtecan (DS-8201a)
other name: (DS-8201a)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marta Vaz Batista, MD
role: Principal Investigator
affiliation: MedSIR
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country: Portugal
country: Spain
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Neoplasms, Second Primary
mesh term: Brain Neoplasms
mesh term: Trastuzumab
mesh term: Trastuzumab deruxtecan