<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/NCT03802084</url>
  </required_header>
  <id_info>
    <org_study_id>4-2018-0807</org_study_id>
    <nct_id>NCT03802084</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Safety and Efficacy of Vactosertib and Imatinib in Patients With Advanced Desmoid Tumor</brief_title>
  <official_title>A Phase 1b/2a, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Vactosertib in Combination With Imatinib in Patients With Advanced Desmoid Tumor (Aggressive Fibromatosis)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hyo Song Kim</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Yonsei University</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 phase I/II, open-label, non-randomized, multicentre study to evaluate the clinical&#xD;
      activity of vactosertib plus imatinib in desmoid tumor. Based on the background, TGF-β&#xD;
      inhibition as a potential therapeutic target for desmoid tumor and convey significant&#xD;
      implications for the clinical development. Therefore, investigator will conduct the phase II&#xD;
      trial of vactosertib in combined with imatinib in desmoid tumor.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Desmoid tumor (aggressive fibromatosis) is a mesenchymal neoplasm associated with mutations,&#xD;
      resulting in -catenin-mediated transcriptional activation. It is composed of a clonal&#xD;
      proliferation of mesenchymal, fibroblast-like cells occurred sporadic or as a part of&#xD;
      familial adenomatosis polyposis. This tumor has high local recurrence rate after complete&#xD;
      excision (~40%). Therefore, although lacking metastatic capability, patients experience&#xD;
      repeated recurrence with attendant severe morbidity. Various systemic therapy using NSAID,&#xD;
      cytotoxic agent (doxorubicin and vinblastine), biologic agents (tamoxifen, low-dose&#xD;
      interferon), and tyrosine kinase inhibitors (imatinib) are recommended with modest activity.&#xD;
      Among them, imatinib has shown promising activity and approved as standard treatment for&#xD;
      desmoid tumor. However, still there is modest response (10-15% responses) and further&#xD;
      combination strategy is warranted to improve antitumor efficacy.&#xD;
&#xD;
      The transforming growth factor-β (TGF-β) family of cytokines has 33 members in humans,&#xD;
      including TGF-β isoforms, activins, bone morphogenetic proteins (BMPs), and growth and&#xD;
      differentiation factors (GDFs). These factors regulate growth, survival, differentiation and&#xD;
      migration of cells, and have important roles during embryonal development and in the control&#xD;
      of adult tissue homeostasis. During carcinogenesis, TGF-β has a dual role; initially it&#xD;
      suppresses tumorigenesis by inducing growth arrest and promoting apoptosis, however, in&#xD;
      advanced cancers, where TGF-β often is overexpressed. In addition, TCGA (the cancer genome&#xD;
      atlas) pan-cancer also demonstrated high expression of TGF-β responsive signature in desmoid&#xD;
      tumor. Regarding the combination, TEW-7197 (vactosertib), a TGF-β inhibitor and imatinib&#xD;
      demonstrated synergistic effect in vitro and xenograft model. Compared to imatinib alone,&#xD;
      administration of imatinib plus vactosertib to mice significantly delayed disease relapse and&#xD;
      prolonged survival. Collectively, these results indicate that vactosertib may be a promising&#xD;
      candidate for a new therapeutic strategy.&#xD;
&#xD;
      Based on the background, TGF-β inhibition as a potential therapeutic target for desmoid tumor&#xD;
      and convey significant implications for the clinical development. Therefore, investigator&#xD;
      will conduct the phase II trial of vactosertib in combined with imatinib in desmoid tumor.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 15, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 1/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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>adverse event</measure>
    <time_frame>4 weeks</time_frame>
    <description>to evaluate the safety and tolerability</description>
  </primary_outcome>
  <primary_outcome>
    <measure>clinical benefit rate was determined using RECIST 1.1</measure>
    <time_frame>16weeks</time_frame>
    <description>to evaluate antitumor activity by determining progression-free survival</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Desmoid Tumor</condition>
  <arm_group>
    <arm_group_label>vactosertib/imatinib combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vactosertib/imatinib combination</intervention_name>
    <description>Phase 1 : Imatinib 400mg QD P q28days Vactosertib 1 cohort 200mg bid (D1-5, 8-12, 15-19, 22-26)&#xD;
1 cohort 100mg bid Phase 2 : Imatinib 400mg QD PO q28days. Vactosertib RP2D, bid (D1-5, 8-12, 15-19, 22-26)</description>
    <arm_group_label>vactosertib/imatinib combination</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed desmoid tumor (aggressive fibromatosis) not available for&#xD;
             local treatment (surgical resection or radiation therapy)&#xD;
&#xD;
          2. Eastern Cooperative Oncology Group performance status of 0-1&#xD;
&#xD;
          3. Measurable lesion (RECIST 1.1.)&#xD;
&#xD;
          4. Patients with sufficient organ function according to laboratory findings&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
               -  Neutrophils ≥ 1000 /µL&#xD;
&#xD;
               -  Platelets ≥ 75,000/µL&#xD;
&#xD;
               -  Total Bilirubin ≤ 1.5 × UNL (upper normal limit): For patients with liver&#xD;
                  metastases, ≤2&#xD;
&#xD;
               -  Serum creatinine ≤1.5 X ULN or &gt; 1.5 X Creatinine Clearance ≥50 mL/min for ULN&#xD;
                  patients (based on 24-hour urinalysis or Cockroft-Gault Formula calculations)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤ 3.0 × UNL or ≤ 5.0 × UNL (for patients with liver or bone&#xD;
                  metastases)&#xD;
&#xD;
               -  Alkaline Phosphatase (ALP): ≤ 3.0 × UNL or ≤ 5.0 × UNL (for patients with liver&#xD;
                  or bone metastases)&#xD;
&#xD;
          5. All patients must be able to provide a newly acquired tumor biopsy during screening&#xD;
             (preferred) or provide an available tumor sample taken ≤3 years prior to screening.&#xD;
&#xD;
          6. Subjects must have ejection fraction ≥ 50% and no clinically significant valvular&#xD;
             dysfunction&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous TGF-β inhibitor exposed patient&#xD;
&#xD;
          2. Patient who has had chemotherapy, radiotherapy, or biological therapy within 2 weeks&#xD;
&#xD;
          3. Any unresolved chronic toxicity greater than grade 2 from previous anticancer therapy.&#xD;
&#xD;
          4. Has an active infection requiring systemic therapy&#xD;
&#xD;
          5. Uncontrolled intercurrent illness, including symptomatic congestive heart failure&#xD;
             (NYHA Class III/IV), uncontrolled hypertension (≥150/90mmHg), unstable angina pectoris&#xD;
             or myocardial infarction (≤ 6 months prior to screening), uncontrolled cardiac&#xD;
             arrhythmia, cardiac valulopathy&#xD;
&#xD;
          6. Uncontrolled or active central nervous system metastasis and/or carcinomatous&#xD;
             meningitis&#xD;
&#xD;
          7. Child-Pugh B or C liver cirrhosis&#xD;
&#xD;
          8. History of another primary malignancy.&#xD;
&#xD;
          9. Female patients who are pregnant or breastfeeding or male or female patients of&#xD;
             reproductive potential who are not willing to employ effective birth control from&#xD;
             screening to 90 days after the last dose of investigational product(IP).&#xD;
&#xD;
         10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of investigational product(IP).&#xD;
&#xD;
         11. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             investigational product(IP).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Severance Hospital, Yonsei University Health System</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>August 29, 2023</last_update_submitted>
  <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Yonsei University</investigator_affiliation>
    <investigator_full_name>Hyo Song Kim</investigator_full_name>
    <investigator_title>professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fibromatosis, Aggressive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Imatinib Mesylate</mesh_term>
    <mesh_term>Vactosertib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03802084
org study id: 4-2018-0807
nct id: NCT03802084
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This is a phase I/II, open-label, non-randomized, multicentre study to evaluate the clinical
      activity of vactosertib plus imatinib in desmoid tumor. Based on the background, TGF-β
      inhibition as a potential therapeutic target for desmoid tumor and convey significant
      implications for the clinical development. Therefore, investigator will conduct the phase II
      trial of vactosertib in combined with imatinib in desmoid tumor.
Desmoid tumor (aggressive fibromatosis) is a mesenchymal neoplasm associated with mutations,
      resulting in -catenin-mediated transcriptional activation. It is composed of a clonal
      proliferation of mesenchymal, fibroblast-like cells occurred sporadic or as a part of
      familial adenomatosis polyposis. This tumor has high local recurrence rate after complete
      excision (~40%). Therefore, although lacking metastatic capability, patients experience
      repeated recurrence with attendant severe morbidity. Various systemic therapy using NSAID,
      cytotoxic agent (doxorubicin and vinblastine), biologic agents (tamoxifen, low-dose
      interferon), and tyrosine kinase inhibitors (imatinib) are recommended with modest activity.
      Among them, imatinib has shown promising activity and approved as standard treatment for
      desmoid tumor. However, still there is modest response (10-15% responses) and further
      combination strategy is warranted to improve antitumor efficacy.

      The transforming growth factor-β (TGF-β) family of cytokines has 33 members in humans,
      including TGF-β isoforms, activins, bone morphogenetic proteins (BMPs), and growth and
      differentiation factors (GDFs). These factors regulate growth, survival, differentiation and
      migration of cells, and have important roles during embryonal development and in the control
      of adult tissue homeostasis. During carcinogenesis, TGF-β has a dual role; initially it
      suppresses tumorigenesis by inducing growth arrest and promoting apoptosis, however, in
      advanced cancers, where TGF-β often is overexpressed. In addition, TCGA (the cancer genome
      atlas) pan-cancer also demonstrated high expression of TGF-β responsive signature in desmoid
      tumor. Regarding the combination, TEW-7197 (vactosertib), a TGF-β inhibitor and imatinib
      demonstrated synergistic effect in vitro and xenograft model. Compared to imatinib alone,
      administration of imatinib plus vactosertib to mice significantly delayed disease relapse and
      prolonged survival. Collectively, these results indicate that vactosertib may be a promising
      candidate for a new therapeutic strategy.

      Based on the background, TGF-β inhibition as a potential therapeutic target for desmoid tumor
      and convey significant implications for the clinical development. Therefore, investigator
      will conduct the phase II trial of vactosertib in combined with imatinib in desmoid tumor.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: adverse event
time frame: 4 weeks
description: to evaluate the safety and tolerability
measure: clinical benefit rate was determined using RECIST 1.1
time frame: 16weeks
description: to evaluate antitumor activity by determining progression-free survival
arm group label: vactosertib/imatinib combination
arm group type: Experimental
intervention type: Drug
intervention name: vactosertib/imatinib combination
description: Phase 1 : Imatinib 400mg QD P q28days Vactosertib 1 cohort 200mg bid (D1-5, 8-12, 15-19, 22-26)
1 cohort 100mg bid Phase 2 : Imatinib 400mg QD PO q28days. Vactosertib RP2D, bid (D1-5, 8-12, 15-19, 22-26)
arm group label: vactosertib/imatinib combination
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Korea, Republic of
responsible party type: Sponsor-Investigator
investigator affiliation: Yonsei University
investigator full name: Hyo Song Kim
investigator title: professor
mesh term: Fibromatosis, Aggressive
mesh term: Imatinib Mesylate
mesh term: Vactosertib
sharing ipd: No