<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/NCT03834948</url>
  </required_header>
  <id_info>
    <org_study_id>AO-176-101</org_study_id>
    <secondary_id>KEYNOTE-C49</secondary_id>
    <nct_id>NCT03834948</nct_id>
  </id_info>
  <brief_title>AO-176 in Multiple Solid Tumor Malignancies</brief_title>
  <official_title>A Phase 1/2 Multicenter, Open-Label, Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of AO-176</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Arch Oncology</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a first-in-human, Phase 1/2 multi-center, open-label, dose escalation and expansion&#xD;
      study of AO-176 which will evaluate the safety, tolerability, pharmacokinetics (PK),&#xD;
      pharmacodynamics, and clinical effects of AO-176 in patients with advanced solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a first-in-human, Phase 1/2 multicenter, open-label, dose escalation and expansion&#xD;
      study of AO-176 in patients with solid tumors. Part A of this study will examine escalating&#xD;
      repeat doses of AO-176 monotherapy in patients with select advanced solid tumors, including&#xD;
      epithelial ovarian carcinoma (EOC), which will include primary peritoneal and fallopian tube&#xD;
      carcinoma; squamous cell carcinoma of the head and neck; endometrial carcinoma; castration&#xD;
      resistant prostate cancer; non-small cell lung adenocarcinoma; papillary thyroid carcinoma;&#xD;
      pleural or peritoneal malignant mesothelioma; and gastroesophageal adenocarcinoma, for which&#xD;
      standard therapy proven to provide clinical benefit does not exist or is no longer effective.&#xD;
&#xD;
      Part B and Part C of this study will examine escalating repeat doses of AO-176 in combination&#xD;
      with paclitaxel (Part B) or pembrolizumab (Part C) in platinum-resistant EOC, including&#xD;
      primary peritoneal and fallopian tube carcinoma; endometrial carcinoma; and gastric&#xD;
      adenocarcinoma/gastroesophageal adenocarcinoma.&#xD;
&#xD;
      The monotherapy and combination dose escalation portions of the study utilize a classic 3+3&#xD;
      design, with enrollment of 3 patients per cohort and expansion of the cohort in the event of&#xD;
      a dose-limiting toxicity (DLT).&#xD;
&#xD;
      Once the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) has been established in&#xD;
      dose escalation, tumor-specific dose expansion cohorts will be recruited to further assess&#xD;
      safety and evaluate preliminary efficacy of AO-176 as monotherapy, in combination with&#xD;
      paclitaxel, and in combination with pembrolizumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 4, 2019</start_date>
  <completion_date type="Actual">February 15, 2023</completion_date>
  <primary_completion_date type="Actual">November 17, 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>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 or AO-176 + paclitaxel or AO-176 + pembrolizumab in a standard 3+3 design; the cohort will be expanded in the event of a DLT.&#xD;
Once the MTD/RP2D has been established for monotherapy, AO-176 + paclitaxel or AO-176 + pembrolizumab, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of AO-176 assessed by adverse events and laboratory abnormalities</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate the safety of AO-176 in combination with paclitaxel measured by the number adverse events, serious adverse events and lab abnormalities.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate the safety of AO-176 in combination with pembrolizumab measured by the number adverse events, serious adverse events and lab abnormalities.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AO-176 anti-tumor activity assessed by changes in response criteria</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate objective response rate of AO-176 using RECIST v1.1 and iRECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate objective response rate of AO-176 in combination with paclitaxel using RECIST v1.1 and iRECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Evaluate objective response rate of AO-176 in combination with pembrolizumab using RECIST v1.1 and iRECIST.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Solid Tumor</condition>
  <arm_group>
    <arm_group_label>AO-176 Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each dose escalation cohort 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 Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AO-176 + Paclitaxel Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and paclitaxel 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 + Paclitaxel Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + paclitaxel.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AO-176 + Pembrolizumab Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and pembrolizumab 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 + Pembrolizumab Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + pembrolizumab.</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</arm_group_label>
    <arm_group_label>AO-176 Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AO-176 + Paclitaxel</intervention_name>
    <description>Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel</description>
    <arm_group_label>AO-176 + Paclitaxel Dose Escalation</arm_group_label>
    <arm_group_label>AO-176 + Paclitaxel Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AO-176 + Pembrolizumab</intervention_name>
    <description>Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab</description>
    <arm_group_label>AO-176 + Pembrolizumab Dose Escalation</arm_group_label>
    <arm_group_label>AO-176 + Pembrolizumab Dose Expansion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria&#xD;
&#xD;
          1. Select advanced solid tumor for which standard therapy proven to provide clinical&#xD;
             benefit does not exist, or is no longer effective&#xD;
&#xD;
             Part A:&#xD;
&#xD;
               -  Epithelial ovarian carcinoma (EOC)&#xD;
&#xD;
               -  Endometrial carcinoma&#xD;
&#xD;
               -  Castration resistant prostate cancer&#xD;
&#xD;
               -  Non-small cell lung adenocarcinoma&#xD;
&#xD;
               -  Papillary thyroid carcinoma&#xD;
&#xD;
               -  Malignant mesothelioma (pleural or peritoneal)&#xD;
&#xD;
               -  Gastroesophageal adenocarcinoma&#xD;
&#xD;
               -  Squamous cell carcinoma of the head and neck&#xD;
&#xD;
             Part B and Part C:&#xD;
&#xD;
               -  Platinum-resistant EOC (including fallopian tube or primary peritoneal cancer)&#xD;
&#xD;
               -  Endometrial carcinoma&#xD;
&#xD;
               -  Gastric adenocarcinoma/gastroesophageal adenocarcinoma&#xD;
&#xD;
          2. Measurable disease&#xD;
&#xD;
          3. ECOG status 0-1&#xD;
&#xD;
          4. Resolution of prior-therapy-related adverse effects&#xD;
&#xD;
          5. Minimum of 4 weeks or 5 half-lives since last dose of cancer therapy&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          1. Previous hypersensitivity reaction to treatment with another monoclonal antibody&#xD;
&#xD;
          2. Unresolved hypersensitivity to paclitaxel or any of its excipients (Part B only).&#xD;
             Patients who have been desensitized may participate.&#xD;
&#xD;
          3. Part C Only&#xD;
&#xD;
               1. History of interstitial lung disease or a history of (non-infectious) pneumonitis&#xD;
                  that required steroids or has current pneumonitis.&#xD;
&#xD;
               2. History of immune mediated colitis, hepatitis, endocrinopathies, nephritis or&#xD;
                  significant immune mediated skin reactions such as toxic epidermal necrolitis or&#xD;
                  Stevens -Johnson Syndrome&#xD;
&#xD;
               3. History of any autoimmune disease which required systemic therapy* in the past 2&#xD;
                  years (i.e., with use of disease modifying agents, corticosteroids or&#xD;
                  immunosuppressive drugs) including but not limited to: i. Inflammatory bowel&#xD;
                  disease (including ulcerative colitis and Crohn's Disease) ii. Rheumatoid&#xD;
                  arthritis iii. Systemic progressive sclerosis (scleroderma) iv. Systemic lupus&#xD;
                  erythematosus v. Autoimmune vasculitis (e.g. Wegener's granulomatosis)&#xD;
                  *Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
                  replacement therapy for adrenal or pituitary insufficiency) is not considered a&#xD;
                  form of systemic treatment and is allowed)&#xD;
&#xD;
          4. Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4 etc.) within 4&#xD;
             weeks prior to the start of study drug&#xD;
&#xD;
          5. Prior treatment with a CD47-targeted therapy&#xD;
&#xD;
          6. Prior organ or stem cell transplant&#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>Benajmin Oshrine, MD</last_name>
    <role>Study Director</role>
    <affiliation>Arch Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Southern California</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215-5450</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oklahoma University, Stephenson Cancer Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center, Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Cancer Specialists</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22031</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwest Medical Specialties</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98405</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>February 4, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</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>CD47</keyword>
  <keyword>AO-176</keyword>
  <keyword>Immunotherapy</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Pembrolizumab</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/NCT03834948
org study id: AO-176-101
secondary id: KEYNOTE-C49
nct id: NCT03834948
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a first-in-human, Phase 1/2 multi-center, open-label, dose escalation and expansion
      study of AO-176 which will evaluate the safety, tolerability, pharmacokinetics (PK),
      pharmacodynamics, and clinical effects of AO-176 in patients with advanced solid tumors.
This is a first-in-human, Phase 1/2 multicenter, open-label, dose escalation and expansion
      study of AO-176 in patients with solid tumors. Part A of this study will examine escalating
      repeat doses of AO-176 monotherapy in patients with select advanced solid tumors, including
      epithelial ovarian carcinoma (EOC), which will include primary peritoneal and fallopian tube
      carcinoma; squamous cell carcinoma of the head and neck; endometrial carcinoma; castration
      resistant prostate cancer; non-small cell lung adenocarcinoma; papillary thyroid carcinoma;
      pleural or peritoneal malignant mesothelioma; and gastroesophageal adenocarcinoma, for which
      standard therapy proven to provide clinical benefit does not exist or is no longer effective.

      Part B and Part C of this study will examine escalating repeat doses of AO-176 in combination
      with paclitaxel (Part B) or pembrolizumab (Part C) in platinum-resistant EOC, including
      primary peritoneal and fallopian tube carcinoma; endometrial carcinoma; and gastric
      adenocarcinoma/gastroesophageal adenocarcinoma.

      The monotherapy and combination dose escalation portions of the study utilize a 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).

      Once the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) has been established in
      dose escalation, tumor-specific dose expansion cohorts will be recruited to further assess
      safety and evaluate preliminary efficacy of AO-176 as monotherapy, in combination with
      paclitaxel, and in combination with pembrolizumab.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: Each dose escalation cohort will initially recruit 3 patients to receive AO-176 or AO-176 + paclitaxel or AO-176 + pembrolizumab in a standard 3+3 design; the cohort will be expanded in the event of a DLT.
Once the MTD/RP2D has been established for monotherapy, AO-176 + paclitaxel or AO-176 + pembrolizumab, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of AO-176 assessed by adverse events and laboratory abnormalities
time frame: Up to 12 months
description: Evaluate the safety of AO-176 measured by the number adverse events, serious adverse events and lab abnormalities.
measure: Safety of AO-176 and paclitaxel assessed by adverse events and laboratory abnormalities
time frame: Up to 12 months
description: Evaluate the safety of AO-176 in combination with paclitaxel measured by the number adverse events, serious adverse events and lab abnormalities.
measure: Safety of AO-176 and pembrolizumab assessed by adverse events and laboratory abnormalities
time frame: Up to 12 months
description: Evaluate the safety of AO-176 in combination with pembrolizumab measured by the number adverse events, serious adverse events and lab abnormalities.
measure: AO-176 anti-tumor activity assessed by changes in response criteria
time frame: Up to 12 months
description: Evaluate objective response rate of AO-176 using RECIST v1.1 and iRECIST.
measure: AO-176 + paclitaxel anti-tumor activity assessed by changes in response criteria
time frame: Up to 12 months
description: Evaluate objective response rate of AO-176 in combination with paclitaxel using RECIST v1.1 and iRECIST.
measure: AO-176 + pembrolizumab anti-tumor activity assessed by changes in response criteria
time frame: Up to 12 months
description: Evaluate objective response rate of AO-176 in combination with pembrolizumab using RECIST v1.1 and iRECIST.
arm group label: AO-176 Dose Escalation
arm group type: Experimental
description: Each dose escalation cohort 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 Dose Expansion
arm group type: Experimental
description: Once the MTD/RP2D has been established, tumor-specific dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efficacy of AO-176.
arm group label: AO-176 + Paclitaxel Dose Escalation
arm group type: Experimental
description: Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and paclitaxel in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
arm group label: AO-176 + Paclitaxel Dose Expansion
arm group type: Experimental
description: Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + paclitaxel.
arm group label: AO-176 + Pembrolizumab Dose Escalation
arm group type: Experimental
description: Each dose escalation cohort will initially recruit 3 patients to receive AO-176 and pembrolizumab in a standard 3+3 design; cohorts will be expanded in the event of a DLT.
arm group label: AO-176 + Pembrolizumab Dose Expansion
arm group type: Experimental
description: Once the MTD/RP2D has been established, tumor-speciﬁc dose expansion cohorts will be recruited to further assess safety and evaluate preliminary efﬁcacy of AO-176 + pembrolizumab.
intervention type: Drug
intervention name: AO-176
description: Humanized monoclonal antibody (mAb) targeting CD47
arm group label: AO-176 Dose Escalation
arm group label: AO-176 Dose Expansion
intervention type: Drug
intervention name: AO-176 + Paclitaxel
description: Humanized monoclonal antibody (mAb) targeting CD47 and paclitaxel
arm group label: AO-176 + Paclitaxel Dose Escalation
arm group label: AO-176 + Paclitaxel Dose Expansion
intervention type: Drug
intervention name: AO-176 + Pembrolizumab
description: Humanized monoclonal antibody (mAb) targeting CD47 and pembrolizumab
arm group label: AO-176 + Pembrolizumab Dose Escalation
arm group label: AO-176 + Pembrolizumab Dose Expansion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Benajmin Oshrine, MD
role: Study Director
affiliation: Arch Oncology
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Paclitaxel
mesh term: Pembrolizumab
sharing ipd: No