<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/NCT04475523</url>
  </required_header>
  <id_info>
    <org_study_id>CI-8993-101</org_study_id>
    <nct_id>NCT04475523</nct_id>
  </id_info>
  <brief_title>Phase 1 Study of CI-8993 Anti-VISTA Antibody in Patients With Advanced Solid Tumor Malignancies</brief_title>
  <official_title>Phase 1 Study of CI-8993 Anti-VISTA Antibody in Patients With Advanced Solid Tumor Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Curis, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Curis, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase 1, open-label, multicenter dose-escalation study to determine the RP2D of CI&#xD;
      8993 for administration to patients with relapsed/refractory solid tumors by evaluating the&#xD;
      safety and tolerability and characterizing the PK, PD, and anti cancer activity of CI-8993 in&#xD;
      this population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The plan is to enroll approximately 50 patients with metastatic or unresectable solid tumor&#xD;
      malignancy (non-lymphoma) that is considered relapsed and/or refractory to prior therapy into&#xD;
      specific dose cohorts to determine the maximum tolerated dose (MTD) of full doses of CI-8993,&#xD;
      based on the occurrence of dose limiting toxicities (DLTs) 28 days from the first full dose.&#xD;
      Administration is every 2 weeks. To assure patient safety, each patient will receive an&#xD;
      initial low dose of CI-8993 (step-dose) one week prior to their first full dose.&#xD;
&#xD;
      A Safety Review Committee (SRC) will review all safety data and make cohort&#xD;
      escalation/de-escalation decisions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 22, 2020</start_date>
  <completion_date type="Anticipated">July 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2023</primary_completion_date>
  <phase>Phase 1</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>Each patient will be administered a step-dose of CI-8993. If a patient experiences a DLT following the step dose, treatment will be discontinued for that patient. If there are no safety concerns following the step dose, the patient will receive the first full dose of CI-8993 a week later. If none of the 3 patients in each cohort (or 1 in 6 patients) experiences a DLT during the first cycle (28 days following the first full dose), the SRC may clear the next dose level for enrollment.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine the maximum tolerated dose of CI-8993</measure>
    <time_frame>2 years</time_frame>
    <description>The highest dose at a schedule, at which the DLT rate during the first cycle of this study (28 days from the first full dose) is &lt; 33% in at least 6 patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Determine the Recommended Phase 2 dose (RP2D)</measure>
    <time_frame>2 years</time_frame>
    <description>The RP2D will be a dose considered to be appropriately safe for a target phase 2 population and exhibit PK and PD characteristics that are favorable and considered likely to support clinical efficacy of CI-8993. The RP2D will be defined by the Safety Review Committee (SRC) based on PK, PD, safety, efficacy results in this study, as well as practical limitations.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Cmax</measure>
    <time_frame>6 months</time_frame>
    <description>maximum serum concentration (Cmax)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Cmin</measure>
    <time_frame>6 months</time_frame>
    <description>trough serum concentration (Cmin)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Tmax</measure>
    <time_frame>6 months</time_frame>
    <description>Time to maximum serum concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Area under the concentration versus time curve (AUC)</measure>
    <time_frame>6 months</time_frame>
    <description>area under the concentration-time curve</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by T 1/2</measure>
    <time_frame>6 months</time_frame>
    <description>Serum terminal elimination half-life (T 1/2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by volume of distribution at steady state</measure>
    <time_frame>6 months</time_frame>
    <description>volume of distribution at steady state (Vdss)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by clearance</measure>
    <time_frame>6 months</time_frame>
    <description>Clearance (CL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess anti-drug antibodies (ADA) of CI-8993</measure>
    <time_frame>6 months</time_frame>
    <description>Evaluate antibodies to CI-8993 in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess objective response rate (ORR)</measure>
    <time_frame>2 years</time_frame>
    <description>Assess with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess duration of response (DOR)</measure>
    <time_frame>2 years</time_frame>
    <description>Assess with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1 )</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate safety of concomitant drugs that are cytochrome P450 (CYP) enzyme substrates with narrow therapeutic index and drug-drug interaction potential</measure>
    <time_frame>2 years</time_frame>
    <description>An analysis of AEs considered related to concomitant drugs that are CYP enzyme substrates with narrow therapeutic index and drug-drug interaction potential</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Solid Tumor</condition>
  <arm_group>
    <arm_group_label>CI-8993 dose escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be administered CI-8993 intravenously at a planned infusion rate over 2 hours at planned step-doses and subsequent full doses. The planned schedule of administration is every 2 weeks. The MTD of full doses of CI-8993 will be determined based on the occurrence of DLTs 28 days from the first full dose. Eligible patients may receive CI-8993 at the dose and schedule, according to their assigned cohorts, until disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CI-8993</intervention_name>
    <description>CI-8993 is a fully human immunoglobulin (Ig) G1κ monoclonal antibody (mAb) against the VISTA ligand</description>
    <arm_group_label>CI-8993 dose escalation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient must be ≥18 years of age&#xD;
&#xD;
          2. Patients must have the following disease related criteria:&#xD;
&#xD;
               -  any type of solid tumor malignancy (non-lymphoma) that is metastatic or&#xD;
                  unresectable and considered relapsed and/or refractory to prior therapy&#xD;
&#xD;
               -  must have evaluable disease.&#xD;
&#xD;
               -  Archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          4. Adequate organ and bone marrow function, in the absence of growth factors.&#xD;
&#xD;
          5. Fertility criteria:&#xD;
&#xD;
               -  Women of childbearing potential (WOCBP) and fertile males with WOCBP partners&#xD;
                  must use highly effective contraception&#xD;
&#xD;
               -  Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted&#xD;
                  reproduction&#xD;
&#xD;
               -  Men must agree not to donate sperm&#xD;
&#xD;
               -  A man who is sexually active with a woman of childbearing potential and has not&#xD;
                  had a vasectomy must agree to use a highly effective method of birth control.&#xD;
&#xD;
          6. Patient must be willing and able to adhere to the prohibitions and restrictions&#xD;
             specified in the protocol. Due to the possibility of neurologic events, patient must&#xD;
             agree to refrain from engaging in hazardous occupations or activities such as&#xD;
             operating heavy or dangerous machinery during the first cycle of treatment.&#xD;
&#xD;
          7. Each patient must sign an informed consent form (ICF) indicating that he or she&#xD;
             understands the purpose and procedures required for the study and is willing to&#xD;
             participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient has any of the following medical situations:&#xD;
&#xD;
               -  Uncontrolled intercurrent illness including, but not limited to: poorly&#xD;
                  controlled hypertension; poorly controlled diabetes; ongoing active infection&#xD;
                  requiring antibiotics or acute infectious illness (including suspected viral&#xD;
                  infection); symptomatic congestive heart failure; unstable angina pectoris;&#xD;
                  cardiac arrhythmia considered to increase risk for the patient by the&#xD;
                  Investigator; psychiatric illness that would limit compliance with study&#xD;
                  requirement&#xD;
&#xD;
               -  Medical illness requiring systemic glucocorticoid use &gt; 10mg/day prednisone&#xD;
                  equivalent.&#xD;
&#xD;
               -  Patients with any CNS disorder, such as CNS malignancy/metastasis, stroke,&#xD;
                  transient ischemic attack, or seizure disorder&#xD;
&#xD;
               -  Personal or familial history of hemophagocytic lymphohistiocytosis or macrophage&#xD;
                  activation syndrome&#xD;
&#xD;
               -  An autoimmune disease with a history of flares requiring immunosuppressant&#xD;
                  medications within the past 6 months&#xD;
&#xD;
               -  Prior allogeneic organ or bone marrow transplant (BMT).&#xD;
&#xD;
               -  Social situation that would limit compliance with study requirements&#xD;
&#xD;
               -  Major surgery (eg, requiring general anesthesia) within 4 weeks before the&#xD;
                  planned first dose of study drug, or not fully recovered from prior surgery, or&#xD;
                  has surgery planned during the time the patient is expected to participate in the&#xD;
                  study or within 4 weeks after the last dose of study drug.&#xD;
&#xD;
               -  History of positive testing for hepatitis B surface antigen (HBsAg) or hepatitis&#xD;
                  C antibody (anti-hepatitis C virus) or other clinically active liver disease, or&#xD;
                  positive testing at screening for HBsAg or anti- hepatitis C virus.&#xD;
&#xD;
               -  History of human immunodeficiency virus (HIV) antibody positive&#xD;
&#xD;
          2. Patient has had prior therapy meeting the following:&#xD;
&#xD;
               -  Anticancer immunotherapy within 3 weeks prior to the first dose of CI-8993&#xD;
&#xD;
               -  Prior T Cell Receptor-modified or chimeric antigen receptor T cell (CART) therapy&#xD;
&#xD;
               -  Other anticancer therapy, including chemotherapy, targeted therapy, or treatment&#xD;
                  with an investigational anticancer agent within 2 weeks prior to the first dose&#xD;
                  of CI-8993&#xD;
&#xD;
               -  Radiotherapy (excluding limited palliative radiation) within 2 weeks of start of&#xD;
                  CI-8993&#xD;
&#xD;
               -  Unresolved toxicities from previous anticancer therapies above Grade 1.&#xD;
&#xD;
               -  Immune-related AE with prior immunotherapy that was Grade 3 or higher.&#xD;
&#xD;
               -  Patient has known allergies, hypersensitivity, or intolerance to components of CI&#xD;
                  8993&#xD;
&#xD;
          3. Patient receiving therapeutic anticoagulants&#xD;
&#xD;
          4. Fertility exclusions:&#xD;
&#xD;
               -  Patient is pregnant, breastfeeding, or planning to become pregnant while enrolled&#xD;
                  in this study or within 3 months after the last dose of study drug; WOCBP must&#xD;
                  have a negative pregnancy status confirmed by serum pregnancy test at screening&#xD;
                  and within 72 hours of first dose of study drug.&#xD;
&#xD;
               -  Patient is a man who plans to father a child while enrolled in this study or&#xD;
                  within 3 months after the last dose of study drug.&#xD;
&#xD;
          5. Vaccinated with a live vaccine within 28 days (with the exception of the annual&#xD;
             inactivated influenza vaccine) prior to the first dose of study drug&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Dartmouth-Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roswell Park Cancer Institute</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Sarah Cannon Research Institute/Tennessee Oncology</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The University of Texas MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peninsula &amp; South Eastern Haematology and Oncology Group</name>
      <address>
        <city>Frankston</city>
        <state>Victoria</state>
        <zip>3199</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>April 21, 2023</last_update_submitted>
  <last_update_submitted_qc>April 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_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/NCT04475523
org study id: CI-8993-101
nct id: NCT04475523
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase 1, open-label, multicenter dose-escalation study to determine the RP2D of CI
      8993 for administration to patients with relapsed/refractory solid tumors by evaluating the
      safety and tolerability and characterizing the PK, PD, and anti cancer activity of CI-8993 in
      this population.
The plan is to enroll approximately 50 patients with metastatic or unresectable solid tumor
      malignancy (non-lymphoma) that is considered relapsed and/or refractory to prior therapy into
      specific dose cohorts to determine the maximum tolerated dose (MTD) of full doses of CI-8993,
      based on the occurrence of dose limiting toxicities (DLTs) 28 days from the first full dose.
      Administration is every 2 weeks. To assure patient safety, each patient will receive an
      initial low dose of CI-8993 (step-dose) one week prior to their first full dose.

      A Safety Review Committee (SRC) will review all safety data and make cohort
      escalation/de-escalation decisions.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Each patient will be administered a step-dose of CI-8993. If a patient experiences a DLT following the step dose, treatment will be discontinued for that patient. If there are no safety concerns following the step dose, the patient will receive the first full dose of CI-8993 a week later. If none of the 3 patients in each cohort (or 1 in 6 patients) experiences a DLT during the first cycle (28 days following the first full dose), the SRC may clear the next dose level for enrollment.
primary purpose: Treatment
masking: None (Open Label)
measure: To determine the maximum tolerated dose of CI-8993
time frame: 2 years
description: The highest dose at a schedule, at which the DLT rate during the first cycle of this study (28 days from the first full dose) is < 33% in at least 6 patients.
measure: Determine the Recommended Phase 2 dose (RP2D)
time frame: 2 years
description: The RP2D will be a dose considered to be appropriately safe for a target phase 2 population and exhibit PK and PD characteristics that are favorable and considered likely to support clinical efficacy of CI-8993. The RP2D will be defined by the Safety Review Committee (SRC) based on PK, PD, safety, efficacy results in this study, as well as practical limitations.
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Cmax
time frame: 6 months
description: maximum serum concentration (Cmax)
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Cmin
time frame: 6 months
description: trough serum concentration (Cmin)
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Tmax
time frame: 6 months
description: Time to maximum serum concentration
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by Area under the concentration versus time curve (AUC)
time frame: 6 months
description: area under the concentration-time curve
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by T 1/2
time frame: 6 months
description: Serum terminal elimination half-life (T 1/2)
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by volume of distribution at steady state
time frame: 6 months
description: volume of distribution at steady state (Vdss)
measure: To characterize the pharmacokinetic (PK) parameters of CI-8993 measured by clearance
time frame: 6 months
description: Clearance (CL)
measure: To assess anti-drug antibodies (ADA) of CI-8993
time frame: 6 months
description: Evaluate antibodies to CI-8993 in serum
measure: To assess objective response rate (ORR)
time frame: 2 years
description: Assess with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
measure: To assess duration of response (DOR)
time frame: 2 years
description: Assess with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1 )
measure: To evaluate safety of concomitant drugs that are cytochrome P450 (CYP) enzyme substrates with narrow therapeutic index and drug-drug interaction potential
time frame: 2 years
description: An analysis of AEs considered related to concomitant drugs that are CYP enzyme substrates with narrow therapeutic index and drug-drug interaction potential
arm group label: CI-8993 dose escalation
arm group type: Experimental
description: Patients will be administered CI-8993 intravenously at a planned infusion rate over 2 hours at planned step-doses and subsequent full doses. The planned schedule of administration is every 2 weeks. The MTD of full doses of CI-8993 will be determined based on the occurrence of DLTs 28 days from the first full dose. Eligible patients may receive CI-8993 at the dose and schedule, according to their assigned cohorts, until disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: CI-8993
description: CI-8993 is a fully human immunoglobulin (Ig) G1κ monoclonal antibody (mAb) against the VISTA ligand
arm group label: CI-8993 dose escalation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
sharing ipd: No