<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/NCT03831295</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-48546</org_study_id>
    <secondary_id>NCI-2019-00251</secondary_id>
    <secondary_id>VAR0175</secondary_id>
    <secondary_id>IRB-48546</secondary_id>
    <nct_id>NCT03831295</nct_id>
  </id_info>
  <brief_title>SD-101 and BMS-986178 in Treating Patients With Advanced or Metastatic Solid Malignancies</brief_title>
  <official_title>Intratumoral Injection of SD-101, an Immunostimulatory CpG Oligonucleotide, in Combination With BMS- 986178, an OX40 Agonist Antibody, in Advanced Solid Malignancies [CA012-014]</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ronald Levy</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects of intratumoral injection of SD-101 and&#xD;
      BMS-986178 in treating patients with solid malignancies that have spread to other places in&#xD;
      the body. The TLR9 agonist SD-101 may stimulate the immune system in different ways and stop&#xD;
      cancer cells from growing. BMS-986178 is a monoclonal anti-OX40 antibody that enhances the&#xD;
      activation of T cells, immune cells that are important for fighting tumors. Giving TLR9&#xD;
      agonist SD-101 together with anti-OX40 antibody BMS-986178 may work better in treating&#xD;
      patients with advanced solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety and tolerability of intratumoral TLR9 agonist SD-101 (SD-101) in&#xD;
      combination with intratumoral and intravenous anti-OX40 antibody BMS 986178 (BMS-986178) in&#xD;
      patients with advanced solid tumors.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
        1. To evaluate the efficacy of treatment with intratumoral SD 101 in combination with&#xD;
           intratumoral and intravenous BMS 986178 in patients with advanced solid tumors.&#xD;
&#xD;
        2. To evaluate changes in pharmacodynamic endpoints in serial tumor biopsies from I TUMOR&#xD;
           treated and untreated sites of disease.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      SAFETY COHORT: Patients receive TLR9 agonist SD-101 intratumorally (IT) on days 1, 8 and 15.&#xD;
      Patients also receive anti-OX40 antibody BMS 986178 IT on days 8 and 15, and intravenously&#xD;
      (IV) over 30 minutes on days 8, 29 and 58.&#xD;
&#xD;
      EXPANSION COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also&#xD;
      receive anti-OX40 antibody BMS 986178 IT on days 1, 8 and 15, and IV over 30 minutes on days&#xD;
      1, 29 and 58.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3-6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 13, 2019</start_date>
  <completion_date type="Actual">October 4, 2021</completion_date>
  <primary_completion_date type="Actual">October 4, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Incidence of adverse events of intratumoral injections of study drugs</measure>
    <time_frame>Up to week 96</time_frame>
    <description>This outcome will be measured for any participant who has received at least one dose of any study medication. Treatment-limiting toxicities will be assessed using CTCAE v5.0. All adverse events will be recorded. Treatment-limiting toxicities are defined as;&#xD;
Hematologic toxicities: Febrile neutropenia; Grade 3 &amp;4 thrombocytopenia; Grade 4 anemia unexplained with exception that toxicities can clearly be determined due to disease progression and/or unrelated to SD-101 or BMS-986178.&#xD;
Non-hematological toxicity ≥ Grade 3; Alopecia; Nausea; Grade 3 or 4 electrolyte abnormalities; Grade 3 or 4 elevation of amylase or lipase not associated with pancreatitis; Grade 3 endocrinopathy controlled by hormone replacement; Grade 3 infusion reaction that returns to Grade 1 in &lt; 6 hours; Grade 3 skin rash not requiring systemic steroid therapy or other systemic immunosuppressive therapy.&#xD;
Doses should be delayed if any Grade ≥ 2 toxicities are not resolved to Grade ≤ 1 or baseline by next cycle.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Tumor response assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions, and assessed by physical measurement; computed tomography (CT), positron emission tomography (PET)-CT.&#xD;
Complete Response (CR) = Disappearance of all target lesions&#xD;
Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions&#xD;
Overall Response (OR) = CR + PR&#xD;
Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)&#xD;
Stable disease (SD) = Small changes that do not meet any of the above criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-Free survival (PFS)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Progression-Free Survival is defined as the time elapsed between treatment initiation (Day 1) and tumor progression or death from any cause. Progression will be defined using RECIST v1.1.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Advanced Malignant Solid Neoplasm</condition>
  <condition>Extracranial Solid Neoplasm</condition>
  <condition>Metastatic Malignant Solid Neoplasm</condition>
  <arm_group>
    <arm_group_label>Treatment (SD-101, BMS-986178)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>SAFETY COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also receive anti-OX40 antibody BMS 986178 IT on days 8 and 15, and IV over 30 minutes on days 8, 29 and 58.&#xD;
EXPANSION COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also receive anti-OX40 antibody BMS 986178 IT on days 1, 8 and 15, and IV over 30 minutes on days 1, 29 and 58.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti-OX40 Antibody BMS 986178</intervention_name>
    <description>Given IT or IV</description>
    <arm_group_label>Treatment (SD-101, BMS-986178)</arm_group_label>
    <other_name>BMS 986178</other_name>
    <other_name>BMS-986178</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TLR9 Agonist SD-101</intervention_name>
    <description>Given IT</description>
    <arm_group_label>Treatment (SD-101, BMS-986178)</arm_group_label>
    <other_name>ISS-ODN SD-101</other_name>
    <other_name>SD-101</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any advanced/metastatic, non-hematological, extracranial solid tumor malignancy with&#xD;
             disease progression after at least one line of standard therapy or for which standard&#xD;
             therapy known to prolong survival does not exist&#xD;
&#xD;
          -  Patients must have at least two sites of non-osseous disease that are ≥10mm in&#xD;
             diameter, one of which must be accessible for intratumoral injection and tumor&#xD;
             biopsies and the other of which must be accessible for needle biopsies by&#xD;
             interventional radiology. (Sites have to be deemed safe for repeated access upon IR&#xD;
             review, based on anatomic location, size, shape, and accessibility). Liver lesions may&#xD;
             not be used as the injection site even if otherwise deemed safe for access.&#xD;
&#xD;
          -  Patients must have at least one additional site of measurable disease by Response&#xD;
             Evaluation Criteria in Solid Tumors (RECIST) criteria, other than the sites selected&#xD;
             for intratumoral injection and tumor biopsies&#xD;
&#xD;
          -  All patients with tumor types for which anti-PD-1 or anti PD-L1 therapy has been&#xD;
             approved should have received such therapy prior to enrollment, with evidence of&#xD;
             progression on at least two scans (ie, with pseudoprogression ruled out). Patients&#xD;
             with validated driver mutations should have received and progressed on appropriate&#xD;
             targeted therapy&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Life expectancy of at least three months&#xD;
&#xD;
          -  Total bilirubin &lt; 1.5 x upper limit of normal (ULN) (unless patient has history of&#xD;
             Gilbert?s disease)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) &lt; 3 x upper limit&#xD;
             of normal (ULN)&#xD;
&#xD;
          -  Creatinine &lt; 1.5 x ULN or measured or calculated creatinine clearance (glomerular&#xD;
             filtration rate [GFR] can also be used in place of creatinine or creatinine [CrCl]) &gt;=&#xD;
             60 mL/min for subject with creatinine levels &gt; 1.5 x ULN&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL without transfusion within the past 4 weeks&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ratio (lNR) within normal limits&#xD;
&#xD;
          -  Written informed consent obtained from subject&#xD;
&#xD;
          -  Patients who have previously received an immune checkpoint inhibitor prior to&#xD;
             enrollment must have any immune related toxicities resolved to =&lt; grade 1 or baseline&#xD;
             (prior to the checkpoint inhibitor) to be eligible. Patients who developed endocrine&#xD;
             adverse events on checkpoint inhibitor are eligible to enter regardless of the Common&#xD;
             Terminology Criteria for Adverse Events (CTCAE) Grade resolution as long as the&#xD;
             patient is well controlled on endocrine replacement&#xD;
&#xD;
          -  Women of childbearing potential must have a urine or serum pregnancy test within 24&#xD;
             hours prior to the first dose of trial treatment. If the urine test is positive or&#xD;
             cannot be confirmed as negative, then a serum test will need to be negative&#xD;
&#xD;
          -  Women of childbearing potential must practice a highly effective method of birth&#xD;
             control during treatment and for 160 days after treatment completion. Women of&#xD;
             childbearing potential who chose complete abstinence must agree to have a urine or&#xD;
             serum pregnancy tests within 24h of each dose of study treatment. If the urine test is&#xD;
             positive or cannot be confirmed as negative, then a serum test will need to be&#xD;
             negative&#xD;
&#xD;
          -  Men who are sexually active with women of childbearing potential must agree to follow&#xD;
             instructions for methods of contraception while being treated on the study, and for&#xD;
             165 days after treatment completion. Men must agree to not donate sperm during this&#xD;
             time period&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of grade 2 or higher hypersensitivity reaction to either SD-101 or BMS-986178&#xD;
&#xD;
          -  Patients who require immediate treatment or cytoreduction, as deemed by their&#xD;
             physician or the study investigators&#xD;
&#xD;
          -  Treatment with other anticancer therapy (chemotherapy, small molecule, or radiation&#xD;
             therapy) within the past 3 weeks prior to study entry or within the past 6 weeks prior&#xD;
             to study entry for immunotherapies&#xD;
&#xD;
          -  Use of investigational agent within the past 3 weeks prior to study enrollment&#xD;
&#xD;
          -  Major surgery within 4 weeks of enrollment, or a wound that has not fully healed&#xD;
&#xD;
          -  Vaccinated with live, attenuated vaccines within 4 weeks of enrollment&#xD;
&#xD;
          -  Symptomatic central nervous system (CNS) metastases&#xD;
&#xD;
          -  Known bleeding disorder that is deemed to place the patient at unacceptable risk for&#xD;
             bleeding complications from intratumoral injection. Patients on anticoagulants and&#xD;
             anti-platelet agents other than aspirin are excluded&#xD;
&#xD;
          -  Any uncontrolled bacterial, fungal, viral, or other infection&#xD;
&#xD;
          -  Active autoimmune disease requiring systemic treatment within the past 2 years, with&#xD;
             the exception of patients well controlled on physiologic endocrine replacement&#xD;
&#xD;
          -  Treatment with corticosteroids (&gt; 10 mg per day prednisone or equivalent) or other&#xD;
             immune suppressive drugs within 14 days prior to initiation of study drug. Steroids&#xD;
             for topical ophthalmic, inhaled, or nasal administration are allowed. Patients&#xD;
             requiring courses of systemic steroids for 14 consecutive days or less for an acute&#xD;
             condition (not for a chronic autoimmune illness) may receive study drug 14 days after&#xD;
             steroid therapy&#xD;
&#xD;
          -  Prior history of cancer that is unlikely to interfere with the ability to give study&#xD;
             treatment or affect the primary outcome or interpretation of the primary outcome of&#xD;
             the study. For a history of malignancy treated with curative intent, enrollment should&#xD;
             occur at least 2 years after such therapy.&#xD;
&#xD;
          -  Significant cardiac disease (New York Heart Association [NYHA] class IV congestive&#xD;
             heart failure, or unstable angina or myocardial infarction within the past 6 months)&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) positive (+) patients or patients with active&#xD;
             hepatitis B or C infection&#xD;
&#xD;
          -  Patients who are pregnant or breastfeeding&#xD;
&#xD;
          -  Any other medical history, including laboratory results, deemed by the investigator&#xD;
             likely to interfere with their participation in the study, or to interfere with the&#xD;
             interpretation of the results&#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>Saad A Khan</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford Cancer Institute Palo Alto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford Cancer Institute Palo Alto</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>February 4, 2019</study_first_submitted>
  <study_first_submitted_qc>February 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 5, 2019</study_first_posted>
  <last_update_submitted>September 14, 2023</last_update_submitted>
  <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Ronald Levy</investigator_full_name>
    <investigator_title>Robert K. and Helen K. Summy Professor in the School of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 15, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/95/NCT03831295/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03831295
org study id: IRB-48546
secondary id: NCI-2019-00251
secondary id: VAR0175
secondary id: IRB-48546
nct id: NCT03831295
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase I trial studies the side effects of intratumoral injection of SD-101 and
      BMS-986178 in treating patients with solid malignancies that have spread to other places in
      the body. The TLR9 agonist SD-101 may stimulate the immune system in different ways and stop
      cancer cells from growing. BMS-986178 is a monoclonal anti-OX40 antibody that enhances the
      activation of T cells, immune cells that are important for fighting tumors. Giving TLR9
      agonist SD-101 together with anti-OX40 antibody BMS-986178 may work better in treating
      patients with advanced solid tumors.
PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of intratumoral TLR9 agonist SD-101 (SD-101) in
      combination with intratumoral and intravenous anti-OX40 antibody BMS 986178 (BMS-986178) in
      patients with advanced solid tumors.

      SECONDARY OBJECTIVES:

        1. To evaluate the efficacy of treatment with intratumoral SD 101 in combination with
           intratumoral and intravenous BMS 986178 in patients with advanced solid tumors.

        2. To evaluate changes in pharmacodynamic endpoints in serial tumor biopsies from I TUMOR
           treated and untreated sites of disease.

      OUTLINE:

      SAFETY COHORT: Patients receive TLR9 agonist SD-101 intratumorally (IT) on days 1, 8 and 15.
      Patients also receive anti-OX40 antibody BMS 986178 IT on days 8 and 15, and intravenously
      (IV) over 30 minutes on days 8, 29 and 58.

      EXPANSION COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also
      receive anti-OX40 antibody BMS 986178 IT on days 1, 8 and 15, and IV over 30 minutes on days
      1, 29 and 58.

      After completion of study treatment, patients are followed up every 3-6 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events of intratumoral injections of study drugs
time frame: Up to week 96
description: This outcome will be measured for any participant who has received at least one dose of any study medication. Treatment-limiting toxicities will be assessed using CTCAE v5.0. All adverse events will be recorded. Treatment-limiting toxicities are defined as;
Hematologic toxicities: Febrile neutropenia; Grade 3 &4 thrombocytopenia; Grade 4 anemia unexplained with exception that toxicities can clearly be determined due to disease progression and/or unrelated to SD-101 or BMS-986178.
Non-hematological toxicity ≥ Grade 3; Alopecia; Nausea; Grade 3 or 4 electrolyte abnormalities; Grade 3 or 4 elevation of amylase or lipase not associated with pancreatitis; Grade 3 endocrinopathy controlled by hormone replacement; Grade 3 infusion reaction that returns to Grade 1 in < 6 hours; Grade 3 skin rash not requiring systemic steroid therapy or other systemic immunosuppressive therapy.
Doses should be delayed if any Grade ≥ 2 toxicities are not resolved to Grade ≤ 1 or baseline by next cycle.
measure: Overall response rate
time frame: Up to 3 years
description: Tumor response assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions, and assessed by physical measurement; computed tomography (CT), positron emission tomography (PET)-CT.
Complete Response (CR) = Disappearance of all target lesions
Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions
Overall Response (OR) = CR + PR
Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)
Stable disease (SD) = Small changes that do not meet any of the above criteria
measure: Progression-Free survival (PFS)
time frame: Up to 3 years
description: Progression-Free Survival is defined as the time elapsed between treatment initiation (Day 1) and tumor progression or death from any cause. Progression will be defined using RECIST v1.1.
arm group label: Treatment (SD-101, BMS-986178)
arm group type: Experimental
description: SAFETY COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also receive anti-OX40 antibody BMS 986178 IT on days 8 and 15, and IV over 30 minutes on days 8, 29 and 58.
EXPANSION COHORT: Patients receive TLR9 agonist SD-101 IT on days 1, 8 and 15. Patients also receive anti-OX40 antibody BMS 986178 IT on days 1, 8 and 15, and IV over 30 minutes on days 1, 29 and 58.
intervention type: Biological
intervention name: Anti-OX40 Antibody BMS 986178
description: Given IT or IV
arm group label: Treatment (SD-101, BMS-986178)
other name: BMS 986178
other name: BMS-986178
intervention type: Drug
intervention name: TLR9 Agonist SD-101
description: Given IT
arm group label: Treatment (SD-101, BMS-986178)
other name: ISS-ODN SD-101
other name: SD-101
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Saad A Khan
role: Principal Investigator
affiliation: Stanford Cancer Institute Palo Alto
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Ronald Levy
investigator title: Robert K. and Helen K. Summy Professor in the School of Medicine
mesh term: Neoplasms
mesh term: Antibodies
sharing ipd: No
provided document: 