<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/NCT04445701</url>
  </required_header>
  <id_info>
    <org_study_id>AO-176-102</org_study_id>
    <nct_id>NCT04445701</nct_id>
  </id_info>
  <brief_title>Study of AO-176 as Monotherapy and in Combination With Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma</brief_title>
  <official_title>A Phase 1/2, Dose Escalation Safety and Tolerability Study of AO-176 as Monotherapy and in Combination With Bortezomib and Dexamethasone in Adults With Relapsed or Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Arch Oncology</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Arch Oncology</source>
  <oversight_info>
    <has_dmc>No</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>
      Open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics&#xD;
      (PK)/pharmacodynamics and initial efficacy of AO-176 as monotherapy and in combination with&#xD;
      dexamethasone and bortezomib in adults with relapsed/refractory multiple myeloma (MM).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      An open-label, multicenter, dose escalation study to evaluate the safety, tolerability and&#xD;
      PK/pharmacodynamics of AO-176 in adults with relapsed/refractory multiple myeloma whose&#xD;
      disease has progressed following at least 3 prior systemic lines of treatment and must have&#xD;
      progressed on the final line of therapy received before being considered for this study.&#xD;
&#xD;
      The study will be conducted in 2 phases; Phase 1 is an ascending-dose study of AO-176&#xD;
      monotherapy utilizing the classic 3+3 design, with enrollment of 3 patients per cohort and&#xD;
      expansion of the cohort in the event of a dose-limiting toxicity (DLT). Following the dose&#xD;
      escalation portion and determination of the monotherapy recommended phase 2 dose (RP2D), an&#xD;
      ascending dose escalation study of AO-176 and dexamethasone combined with bortezomib will be&#xD;
      evaluated utilizing the same 3+3 dose escalation design.&#xD;
&#xD;
      Phase 2 will evaluate the clinical activity of AO-176 plus dexamethasone and bortezomib at&#xD;
      the RP2D as determined in Phase 1 Part 2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 30, 2020</start_date>
  <completion_date type="Actual">November 14, 2022</completion_date>
  <primary_completion_date type="Actual">August 5, 2022</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>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Phase 1 Part 1: Up to 4 dose escalation cohorts will be enrolled; each cohort will initially recruit 3 patients to receive AO-176 monotherapy in a standard 3+3 design; the cohort will be expanded in the event of a DLT. Once the RP2D has been identified, an expansion cohort will be enrolled to evaluate AO-176 at the RP2D in combination with dexamethasone (DEX).&#xD;
Phase 1 Part 2: Dose escalation cohorts will evaluate AO-176 in combination with DEX and bortezomib (BORT) to determine the RP2D of AO-176 + DEX + BORT in a standard 3+3 design; the cohort will be expanded in the event of a DLT.&#xD;
Phase 2: Up to 48 patients will be enrolled to evaluate the preliminary efficacy of AO-176 + DEX + BORT using a Simon 2-stage design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase 1: MTD / RP2D of AO-176 assessed by incidence of dose-limiting toxicities and incidence of treatment-related adverse events (TEAEs) as assessed by CTCAE v5.0</measure>
    <time_frame>12 months</time_frame>
    <description>Safety and tolerability of AO-176 when administered as monotherapy and in combination with dexamethasone or with dexamethasone plus bortezomib in adult patients with R/R MM as assessed by incidence of DLTs and TEAEs as assessed by CTCAE v5.0</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: Objective response rate (ORR) of AO-176 + DEX + BORT</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on ORR using International Myeloma Working Group (IMWG) uniform response criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase 1: ORR of single agent AO-176</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of single agent AO-176 based on ORR using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1: Duration of response (DOR) of single agent AO-176</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of single agent AO-176 based on DOR using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1: Disease control rate (DCR) of single agent AO-176</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of single agent AO-176 based on DCR using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1: Progression-free survival (PFS) of single agent AO-176</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of single agent AO-176 based on PFS using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1: Overall survival (OS) of single agent AO-176</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of single agent AO-176 based on OS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 2: DOR of AO-176 + DEX + BORT</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DOR using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 2: DCR of AO-176 + DEX + BORT</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DCR using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 2: PFS of AO-176 + DEX + BORT</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on PFS using IMWG uniform response criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 2: OS of AO-176 + DEX + BORT</measure>
    <time_frame>12 months</time_frame>
    <description>Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>AO-176 Dose Escalation Monotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The dose escalation monotherapy cohorts will initially recruit 3 patients to receive AO-176 in a standard 3+3 design; cohorts will be expanded in the event of a DLT.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AO-176 + DEX Expansion Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once the monotherapy RP2D has been established, an expansion cohort of AO-176 + dexamethasone will be enrolled.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AO-176 + DEX + BORT Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Following evaluation of AO-176 + dexamethasone, dose escalation cohorts of AO-176 + dexamethasone + bortezomib will be enrolled. Each dose escalation cohort will initially recruit 3 patients in a standard 3+3 design; cohorts will be expanded in the event of a DLT. The Phase 2 portion of the study will further evaluate the RP2D of AO-176 + DEX + BORT.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AO-176</intervention_name>
    <description>Humanized monoclonal antibody (mAb) targeting CD47</description>
    <arm_group_label>AO-176 Dose Escalation Monotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AO-176 + Dex</intervention_name>
    <description>Humanized mAb targeting CD47 plus dexamethasone</description>
    <arm_group_label>AO-176 + DEX Expansion Cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AO-176 + Dex + Bort</intervention_name>
    <description>Humanized mAb targeting CD47 plus dexamethasone plus bortezomib</description>
    <arm_group_label>AO-176 + DEX + BORT Dose Escalation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          1. Confirmed diagnosis of symptomatic MM per IMWG criteria&#xD;
&#xD;
          2. Measurable disease&#xD;
&#xD;
          3. Relapsed or refractory to at least 3 prior systemic lines of therapy for MM&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) status 0-2&#xD;
&#xD;
          5. Resolution of prior therapy-related adverse events&#xD;
&#xD;
          6. Minimum of 2 weeks since last dose of cancer therapy or radiotherapy&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          1. Previous Grade 3-4 infusion or hypersensitivity reaction&#xD;
&#xD;
          2. Severe asthma or chronic obstructive pulmonary disease exacerbations requiring&#xD;
             hospital admission or steroids&#xD;
&#xD;
          3. Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1 or CTLA-4) within 4&#xD;
             weeks.&#xD;
&#xD;
          4. Prior treatment with a therapeutic agent that targets the CD47 axis.&#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>Ben Oshrine, MD</last_name>
    <role>Study Director</role>
    <affiliation>Sr Medical Director, Arch Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin and Froedtert Hospital</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>August 21, 2023</last_update_submitted>
  <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>AO-176</keyword>
  <keyword>CD47</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Monoclonal antibody</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</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/NCT04445701
org study id: AO-176-102
nct id: NCT04445701
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics
      (PK)/pharmacodynamics and initial efficacy of AO-176 as monotherapy and in combination with
      dexamethasone and bortezomib in adults with relapsed/refractory multiple myeloma (MM).
An open-label, multicenter, dose escalation study to evaluate the safety, tolerability and
      PK/pharmacodynamics of AO-176 in adults with relapsed/refractory multiple myeloma whose
      disease has progressed following at least 3 prior systemic lines of treatment and must have
      progressed on the final line of therapy received before being considered for this study.

      The study will be conducted in 2 phases; Phase 1 is an ascending-dose study of AO-176
      monotherapy utilizing the classic 3+3 design, with enrollment of 3 patients per cohort and
      expansion of the cohort in the event of a dose-limiting toxicity (DLT). Following the dose
      escalation portion and determination of the monotherapy recommended phase 2 dose (RP2D), an
      ascending dose escalation study of AO-176 and dexamethasone combined with bortezomib will be
      evaluated utilizing the same 3+3 dose escalation design.

      Phase 2 will evaluate the clinical activity of AO-176 plus dexamethasone and bortezomib at
      the RP2D as determined in Phase 1 Part 2.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: Phase 1 Part 1: Up to 4 dose escalation cohorts will be enrolled; each cohort will initially recruit 3 patients to receive AO-176 monotherapy in a standard 3+3 design; the cohort will be expanded in the event of a DLT. Once the RP2D has been identified, an expansion cohort will be enrolled to evaluate AO-176 at the RP2D in combination with dexamethasone (DEX).
Phase 1 Part 2: Dose escalation cohorts will evaluate AO-176 in combination with DEX and bortezomib (BORT) to determine the RP2D of AO-176 + DEX + BORT in a standard 3+3 design; the cohort will be expanded in the event of a DLT.
Phase 2: Up to 48 patients will be enrolled to evaluate the preliminary efficacy of AO-176 + DEX + BORT using a Simon 2-stage design.
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 1: MTD / RP2D of AO-176 assessed by incidence of dose-limiting toxicities and incidence of treatment-related adverse events (TEAEs) as assessed by CTCAE v5.0
time frame: 12 months
description: Safety and tolerability of AO-176 when administered as monotherapy and in combination with dexamethasone or with dexamethasone plus bortezomib in adult patients with R/R MM as assessed by incidence of DLTs and TEAEs as assessed by CTCAE v5.0
measure: Phase 2: Objective response rate (ORR) of AO-176 + DEX + BORT
time frame: 12 months
description: Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on ORR using International Myeloma Working Group (IMWG) uniform response criteria
measure: Phase 1: ORR of single agent AO-176
time frame: 12 months
description: Evaluate the clinical activity of single agent AO-176 based on ORR using IMWG uniform response criteria
measure: Phase 1: Duration of response (DOR) of single agent AO-176
time frame: 12 months
description: Evaluate the clinical activity of single agent AO-176 based on DOR using IMWG uniform response criteria
measure: Phase 1: Disease control rate (DCR) of single agent AO-176
time frame: 12 months
description: Evaluate the clinical activity of single agent AO-176 based on DCR using IMWG uniform response criteria
measure: Phase 1: Progression-free survival (PFS) of single agent AO-176
time frame: 12 months
description: Evaluate the clinical activity of single agent AO-176 based on PFS using IMWG uniform response criteria
measure: Phase 1: Overall survival (OS) of single agent AO-176
time frame: 12 months
description: Evaluate the clinical activity of single agent AO-176 based on OS
measure: Phase 2: DOR of AO-176 + DEX + BORT
time frame: 12 months
description: Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DOR using IMWG uniform response criteria
measure: Phase 2: DCR of AO-176 + DEX + BORT
time frame: 12 months
description: Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on DCR using IMWG uniform response criteria
measure: Phase 2: PFS of AO-176 + DEX + BORT
time frame: 12 months
description: Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on PFS using IMWG uniform response criteria
measure: Phase 2: OS of AO-176 + DEX + BORT
time frame: 12 months
description: Evaluate the clinical activity of AO-176 + dexamethasone + bortezomib based on OS
arm group label: AO-176 Dose Escalation Monotherapy
arm group type: Experimental
description: The dose escalation monotherapy cohorts will initially recruit 3 patients to receive AO-176 in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
arm group label: AO-176 + DEX Expansion Cohort
arm group type: Experimental
description: Once the monotherapy RP2D has been established, an expansion cohort of AO-176 + dexamethasone will be enrolled.
arm group label: AO-176 + DEX + BORT Dose Escalation
arm group type: Experimental
description: Following evaluation of AO-176 + dexamethasone, dose escalation cohorts of AO-176 + dexamethasone + bortezomib will be enrolled. Each dose escalation cohort will initially recruit 3 patients in a standard 3+3 design; cohorts will be expanded in the event of a DLT. The Phase 2 portion of the study will further evaluate the RP2D of AO-176 + DEX + BORT.
intervention type: Drug
intervention name: AO-176
description: Humanized monoclonal antibody (mAb) targeting CD47
arm group label: AO-176 Dose Escalation Monotherapy
intervention type: Drug
intervention name: AO-176 + Dex
description: Humanized mAb targeting CD47 plus dexamethasone
arm group label: AO-176 + DEX Expansion Cohort
intervention type: Drug
intervention name: AO-176 + Dex + Bort
description: Humanized mAb targeting CD47 plus dexamethasone plus bortezomib
arm group label: AO-176 + DEX + BORT Dose Escalation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ben Oshrine, MD
role: Study Director
affiliation: Sr Medical Director, Arch Oncology
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
sharing ipd: No