<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/NCT02254772</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-31133</org_study_id>
    <secondary_id>NCI-2014-01978</secondary_id>
    <secondary_id>LYMNHL0119</secondary_id>
    <secondary_id>5R01CA188005-02</secondary_id>
    <nct_id>NCT02254772</nct_id>
  </id_info>
  <brief_title>A Phase I/II Study of Intratumoral Injection of SD-101</brief_title>
  <official_title>A Phase I/II Study of Intratumoral Injection of SD-101, an Immunostimulatory CpG, and Intratumoral Injection of Ipilimumab, an Anti-CTLA4 Monoclonal Antibody, in Combination With Local Radiation in Low-Grade B-Cell Lymphomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Robert Lowsky</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase 1-2 trial studies the side effects and best dose of ipilimumab in combination with&#xD;
      toll-like receptor 9 (TLR9) agonist SD-101 and radiation therapy in treating patients with&#xD;
      recurrent low-grade B-cell lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Monoclonal antibodies, such as ipilimumab, may block cancer growth in different ways by&#xD;
      targeting certain cells. Biological therapies, such as TLR9 agonist SD-101, use substances&#xD;
      made from living organisms that may stimulate or suppress the immune system in different ways&#xD;
      and stop cancer cells from growing. Radiation therapy uses high energy x-rays to kill cancer&#xD;
      cells and shrink tumors. Giving ipilimumab in combination with TLR9 agonist SD-101 and&#xD;
      radiation therapy may be a better treatment for B-cell lymphoma.&#xD;
&#xD;
      Study objectives are dose-limiting toxicity (DLT) and the treatment assessments tumor&#xD;
      response and time-to-progression. Cohort 1 dose level is 10 mg ipilimumab, subsequent cohort&#xD;
      is 5 or 25 mg ipilimumab.&#xD;
&#xD;
        -  If 2 out of 6 patients experience a DLT in the first cohort (10 mg ipilimumab), the dose&#xD;
           will be de-escalated to 5 mg (&quot;Cohort -1&quot;).&#xD;
&#xD;
        -  If 2 out of 6 patients experience a DLT at the 5 mg dose level, then the study will be&#xD;
           stopped.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">January 26, 2017</completion_date>
  <primary_completion_date type="Actual">November 10, 2016</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week)</measure>
    <time_frame>Up to 10 weeks</time_frame>
    <description>To determine the safety and tolerability of SD-101 (1 mg/week) and local low dose radiation plus escalating doses of subcutaneously (SC)-administered ipilimumab, the incidence of dose-limiting toxicities (DLT) will be assessed according to the following DLT definitions. Related adverse events (AEs) are toxicities. &quot;Treatment&quot; includes radiation therapy.&#xD;
Grade 4 treatment-related AE&#xD;
Any drug-related AE ≥ Grade 3, including injection site reaction&#xD;
≥ Grade 3 treatment-related clinical autoimmune reaction involving major organs (defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow, eye, or central nervous system) which does not resolve to baseline or Grade 1 within 6 weeks&#xD;
Treatment-related AE ≥ Grade 3 that persists despite adequate/maximal medical therapy and/or prophylaxis, EXCEPT&#xD;
Treatment-related skin rash ≤ Grade 3, that does not require systemic steroid therapy or other immunosuppressive therapy OR&#xD;
Grade 3 flu-like AEs&#xD;
Uveitis ≥ Grade 2</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tumor Response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Tumor response was assessed per the Cheson Criteria for low-grade B-cell lymphomas.&#xD;
Complete Response (CR) - No evidence disease. Partial Response (PR) - Regression of measurable disease with no new sites Progressive Disease (PD) - Any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.&#xD;
Stable Disease (SD) - Any status that is not CR; PR; or PD. See references (Cheson BD, et al. J Clin Oncol. Apr 1999;17(4):1244. PubMed ID 10561185.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Time to Progression (TTP)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue</condition>
  <condition>Nodal Marginal Zone B-cell Lymphoma</condition>
  <condition>Recurrent Grade 1 Follicular Lymphoma</condition>
  <condition>Recurrent Grade 2 Follicular Lymphoma</condition>
  <condition>Recurrent Marginal Zone Lymphoma</condition>
  <condition>Recurrent Small Lymphocytic Lymphoma</condition>
  <condition>Splenic Marginal Zone Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>A dose of 10 mg in cohort 1 or 25mg in cohort 2 via intratumoral injection on day 2, week 1.</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Yervoy</other_name>
    <other_name>MDX-010</other_name>
    <other_name>MDX-CTLA-4</other_name>
    <other_name>monoclonal antibody CTLA-4</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SD-101</intervention_name>
    <description>Started on day 2 week 1, then once every week x 4 successive weeks for a total of 5 injections.</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>ISS-ODN SD-101</other_name>
    <other_name>TLR9 agonist</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation therapy</intervention_name>
    <description>Undergo low-dose radiation therapy to 1 site of disease</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Irradiation</other_name>
    <other_name>Radiotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  Biopsy-confirmed low-grade B-cell lymphoma, specifically, follicular grade 1 or 2, or&#xD;
             3A marginal zone or small lymphocytic lymphoma; patients must have relapsed from or&#xD;
             are refractory to prior therapy&#xD;
&#xD;
          -  Patients must have at least one site of disease that is accessible for intratumoral&#xD;
             injection of SD-101 and of ipilimumab (diameter ≥ 10mm), percutaneously&#xD;
&#xD;
          -  Tumor specimens must be available for immunological studies either from a previous&#xD;
             biopsy or a new biopsy obtained before the initiation of the study&#xD;
&#xD;
          -  Patients must have measurable disease other than the injection site or biopsy site&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 [corresponds to&#xD;
             Karnofsky Performance Status (KPS) of ≥ 70]&#xD;
&#xD;
          -  White blood cell count (WBC) ≥ 2000/µL (2 x 10^9/L)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥ 1000/µL (0.5 x 10^9/L)&#xD;
&#xD;
          -  Platelets ≥ 75 x 10^3/µL (75 x 10^9/L)&#xD;
&#xD;
          -  Hemoglobin ≥ 8 g/dL (may be transfused)&#xD;
&#xD;
          -  Creatinine ≤ 2.0 x upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN for&#xD;
             subjects without liver metastasis; ≤ 5 times for liver metastases&#xD;
&#xD;
          -  Bilirubin ≤ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must have a&#xD;
             total bilirubin of less than 3.0 mg/dL)&#xD;
&#xD;
          -  No active or chronic infection with human immunodeficiency virus (HIV), Hepatitis B,&#xD;
             or Hepatitis C&#xD;
&#xD;
          -  Must be at least 4 weeks since treatment with standard or investigational&#xD;
             chemotherapy, biochemotherapy, surgery, radiation, cytokine therapy, and 8 weeks since&#xD;
             any monoclonal antibodies or immunotherapy, and recovered from any clinically&#xD;
             significant toxicity experienced during treatment&#xD;
&#xD;
          -  Patients of reproductive potential must agree to use an effective (&gt; 90% reliability)&#xD;
             form of contraception during the study and for 6 months following the last study drug&#xD;
             administration&#xD;
&#xD;
          -  Women of reproductive potential must have negative urine pregnancy test&#xD;
&#xD;
          -  Life expectancy greater than 4 months&#xD;
&#xD;
          -  Able to comply with the treatment schedule&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Pre-existing autoimmune or antibody mediated disease including systemic lupus&#xD;
             erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome,&#xD;
             autoimmune thrombocytopenia, Addison's disease, but excluding the presence of&#xD;
             auto-antibodies without clinical autoimmune disease&#xD;
&#xD;
          -  History of inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis),&#xD;
             celiac disease, or other chronic gastrointestinal conditions associated with diarrhea,&#xD;
             or current acute colitis of any origin&#xD;
&#xD;
          -  Any history of diverticulitis, or evidence of diverticulitis at baseline, including&#xD;
             evidence limited to computed tomography (CT) scan only (note diverticulosis is not an&#xD;
             exclusion criterion)&#xD;
&#xD;
          -  Severe psoriasis&#xD;
&#xD;
          -  Active thyroiditis&#xD;
&#xD;
          -  History of uveitis&#xD;
&#xD;
          -  Known history of HIV; patients with Acquired Immunodeficiency Syndrome (AIDS) are&#xD;
             excluded&#xD;
&#xD;
          -  Patients with active infection or with a fever &gt; 38.5 degrees C within 3 days prior to&#xD;
             the first scheduled treatment&#xD;
&#xD;
          -  Central nervous system (CNS) lymphoma&#xD;
&#xD;
          -  Prior malignancy (active within 5 years of screening) except basal cell or completely&#xD;
             excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell&#xD;
             carcinoma of the cervix&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar composition to SD-101&#xD;
             or ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] antibodies)&#xD;
&#xD;
          -  Current anticoagulant therapy (EXCEPTION acetylsalicylic acid ≤ 325 mg per day&#xD;
             allowed)&#xD;
&#xD;
          -  Treatment with an immunosuppressive regimen of corticosteroids or other&#xD;
             immunosuppressive medication (eg, methotrexate, rapamycin) within 30 days of study&#xD;
             treatment; note patients with adrenal insufficiency may take up to 5 mg of prednisone&#xD;
             or equivalent daily; topical and inhaled corticosteroids in standard doses are allowed&#xD;
&#xD;
          -  Significant cardiovascular disease [ie, New York Heart Association (NYHA) class 3&#xD;
             congestive heart failure; myocardial infarction with the past 6 months; unstable&#xD;
             angina; coronary angioplasty with the past 6 months; uncontrolled atrial or&#xD;
             ventricular cardiac arrhythmias]&#xD;
&#xD;
          -  Pregnant or lactating&#xD;
&#xD;
          -  Any other medical history, including laboratory results, deemed by the investigator to&#xD;
             be 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>Ronald Levy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University Hospitals and Clinics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University Hospitals and Clinics</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. doi: 10.1200/JCO.1999.17.4.1244. Erratum In: J Clin Oncol 2000 Jun;18(11):2351.</citation>
    <PMID>10561185</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>September 29, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <results_first_submitted>September 4, 2017</results_first_submitted>
  <results_first_submitted_qc>September 4, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">September 29, 2017</results_first_posted>
  <last_update_submitted>November 17, 2019</last_update_submitted>
  <last_update_submitted_qc>November 17, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Robert Lowsky</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, B-Cell, Marginal Zone</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
          <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Ineligible</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
          <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week)</title>
        <description>To determine the safety and tolerability of SD-101 (1 mg/week) and local low dose radiation plus escalating doses of subcutaneously (SC)-administered ipilimumab, the incidence of dose-limiting toxicities (DLT) will be assessed according to the following DLT definitions. Related adverse events (AEs) are toxicities. &quot;Treatment&quot; includes radiation therapy.&#xD;
Grade 4 treatment-related AE&#xD;
Any drug-related AE ≥ Grade 3, including injection site reaction&#xD;
≥ Grade 3 treatment-related clinical autoimmune reaction involving major organs (defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow, eye, or central nervous system) which does not resolve to baseline or Grade 1 within 6 weeks&#xD;
Treatment-related AE ≥ Grade 3 that persists despite adequate/maximal medical therapy and/or prophylaxis, EXCEPT&#xD;
Treatment-related skin rash ≤ Grade 3, that does not require systemic steroid therapy or other immunosuppressive therapy OR&#xD;
Grade 3 flu-like AEs&#xD;
Uveitis ≥ Grade 2</description>
        <time_frame>Up to 10 weeks</time_frame>
        <population>Only the starting dose level of 10 mg ipilimumab plus SD-101 (1 mg/week) was evaluated. The dose level of ipilimumab could not be escalated due to inability to obtain a higher concentration of ipilimumab.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
            <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week)</title>
          <description>To determine the safety and tolerability of SD-101 (1 mg/week) and local low dose radiation plus escalating doses of subcutaneously (SC)-administered ipilimumab, the incidence of dose-limiting toxicities (DLT) will be assessed according to the following DLT definitions. Related adverse events (AEs) are toxicities. &quot;Treatment&quot; includes radiation therapy.&#xD;
Grade 4 treatment-related AE&#xD;
Any drug-related AE ≥ Grade 3, including injection site reaction&#xD;
≥ Grade 3 treatment-related clinical autoimmune reaction involving major organs (defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow, eye, or central nervous system) which does not resolve to baseline or Grade 1 within 6 weeks&#xD;
Treatment-related AE ≥ Grade 3 that persists despite adequate/maximal medical therapy and/or prophylaxis, EXCEPT&#xD;
Treatment-related skin rash ≤ Grade 3, that does not require systemic steroid therapy or other immunosuppressive therapy OR&#xD;
Grade 3 flu-like AEs&#xD;
Uveitis ≥ Grade 2</description>
          <population>Only the starting dose level of 10 mg ipilimumab plus SD-101 (1 mg/week) was evaluated. The dose level of ipilimumab could not be escalated due to inability to obtain a higher concentration of ipilimumab.</population>
          <units>Dose-limiting toxicity events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tumor Response</title>
        <description>Tumor response was assessed per the Cheson Criteria for low-grade B-cell lymphomas.&#xD;
Complete Response (CR) - No evidence disease. Partial Response (PR) - Regression of measurable disease with no new sites Progressive Disease (PD) - Any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.&#xD;
Stable Disease (SD) - Any status that is not CR; PR; or PD. See references (Cheson BD, et al. J Clin Oncol. Apr 1999;17(4):1244. PubMed ID 10561185.</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Note that 1 participants initially experienced a partial response (PR), but later had progressive disease (PD).</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
            <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Tumor Response</title>
          <description>Tumor response was assessed per the Cheson Criteria for low-grade B-cell lymphomas.&#xD;
Complete Response (CR) - No evidence disease. Partial Response (PR) - Regression of measurable disease with no new sites Progressive Disease (PD) - Any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.&#xD;
Stable Disease (SD) - Any status that is not CR; PR; or PD. See references (Cheson BD, et al. J Clin Oncol. Apr 1999;17(4):1244. PubMed ID 10561185.</description>
          <population>Note that 1 participants initially experienced a partial response (PR), but later had progressive disease (PD).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response (CR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response (PR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease (SD)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease (PD)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Time to Progression (TTP)</title>
        <description>Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.</description>
        <time_frame>Up to 2 years</time_frame>
        <population>1 participant had stable disease, but did not provide a final follow-up at 2 years.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
            <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Time to Progression (TTP)</title>
          <description>Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.</description>
          <population>1 participant had stable disease, but did not provide a final follow-up at 2 years.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.33" lower_limit="0.53" upper_limit="12.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment (SD-101 + Ipilimumab + Radiation)</title>
          <description>Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="13" subjects_affected="9" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Swelling</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Flu Like Symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Increased Creatinine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Induration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Ronald Levy, MD, Professor of Medicine</name_or_title>
      <organization>Stanford Univeristy Medical Center</organization>
      <phone>650-725-6452</phone>
      <email>levy@stanford.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02254772
org study id: IRB-31133
secondary id: NCI-2014-01978
secondary id: LYMNHL0119
secondary id: 5R01CA188005-02
nct id: NCT02254772
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase 1-2 trial studies the side effects and best dose of ipilimumab in combination with
      toll-like receptor 9 (TLR9) agonist SD-101 and radiation therapy in treating patients with
      recurrent low-grade B-cell lymphoma.
Monoclonal antibodies, such as ipilimumab, may block cancer growth in different ways by
      targeting certain cells. Biological therapies, such as TLR9 agonist SD-101, use substances
      made from living organisms that may stimulate or suppress the immune system in different ways
      and stop cancer cells from growing. Radiation therapy uses high energy x-rays to kill cancer
      cells and shrink tumors. Giving ipilimumab in combination with TLR9 agonist SD-101 and
      radiation therapy may be a better treatment for B-cell lymphoma.

      Study objectives are dose-limiting toxicity (DLT) and the treatment assessments tumor
      response and time-to-progression. Cohort 1 dose level is 10 mg ipilimumab, subsequent cohort
      is 5 or 25 mg ipilimumab.

        -  If 2 out of 6 patients experience a DLT in the first cohort (10 mg ipilimumab), the dose
           will be de-escalated to 5 mg ("Cohort -1").

        -  If 2 out of 6 patients experience a DLT at the 5 mg dose level, then the study will be
           stopped.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Dose-limiting Toxicity (DLT) Events of Ipilimumab Plus a Fixed Dose of SD-101 (1 mg/Week)
time frame: Up to 10 weeks
description: To determine the safety and tolerability of SD-101 (1 mg/week) and local low dose radiation plus escalating doses of subcutaneously (SC)-administered ipilimumab, the incidence of dose-limiting toxicities (DLT) will be assessed according to the following DLT definitions. Related adverse events (AEs) are toxicities. "Treatment" includes radiation therapy.
Grade 4 treatment-related AE
Any drug-related AE ≥ Grade 3, including injection site reaction
≥ Grade 3 treatment-related clinical autoimmune reaction involving major organs (defined as liver, pancreas, lung, heart, kidney, bowel, bone marrow, eye, or central nervous system) which does not resolve to baseline or Grade 1 within 6 weeks
Treatment-related AE ≥ Grade 3 that persists despite adequate/maximal medical therapy and/or prophylaxis, EXCEPT
Treatment-related skin rash ≤ Grade 3, that does not require systemic steroid therapy or other immunosuppressive therapy OR
Grade 3 flu-like AEs
Uveitis ≥ Grade 2
measure: Tumor Response
time frame: Up to 2 years
description: Tumor response was assessed per the Cheson Criteria for low-grade B-cell lymphomas.
Complete Response (CR) - No evidence disease. Partial Response (PR) - Regression of measurable disease with no new sites Progressive Disease (PD) - Any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.
Stable Disease (SD) - Any status that is not CR; PR; or PD. See references (Cheson BD, et al. J Clin Oncol. Apr 1999;17(4):1244. PubMed ID 10561185.
measure: Median Time to Progression (TTP)
time frame: Up to 2 years
description: Tumor progression was assessed as any new lesion or increase by ≥ 50% of any previously-involved site after treatment nadir.
arm group label: Treatment
arm group type: Experimental
description: Patients receive TLR9 agonist SD-101 via intratumoral injections; ipilimumab via intratumoral injection; and undergo radiation therapy on days 1 and 2.
intervention type: Biological
intervention name: Ipilimumab
description: A dose of 10 mg in cohort 1 or 25mg in cohort 2 via intratumoral injection on day 2, week 1.
arm group label: Treatment
other name: Yervoy
other name: MDX-010
other name: MDX-CTLA-4
other name: monoclonal antibody CTLA-4
intervention type: Drug
intervention name: SD-101
description: Started on day 2 week 1, then once every week x 4 successive weeks for a total of 5 injections.
arm group label: Treatment
other name: ISS-ODN SD-101
other name: TLR9 agonist
intervention type: Radiation
intervention name: Radiation therapy
description: Undergo low-dose radiation therapy to 1 site of disease
arm group label: Treatment
other name: Irradiation
other name: Radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ronald Levy, MD
role: Principal Investigator
affiliation: Stanford University Hospitals and Clinics
facility: 
country: United States
citation: Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. doi: 10.1200/JCO.1999.17.4.1244. Erratum In: J Clin Oncol 2000 Jun;18(11):2351.
PMID: 10561185
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Robert Lowsky
investigator title: Professor of Medicine
mesh term: Lymphoma
mesh term: Lymphoma, Follicular
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, B-Cell, Marginal Zone
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Recurrence
mesh term: Ipilimumab
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 